U.S. patent application number 12/429703 was filed with the patent office on 2010-02-11 for covalently grafted pharmaceutically active polymers.
This patent application is currently assigned to Interface Biologics, Inc.. Invention is credited to Fan Gu, Frank Laronde.
Application Number | 20100034862 12/429703 |
Document ID | / |
Family ID | 41216380 |
Filed Date | 2010-02-11 |
United States Patent
Application |
20100034862 |
Kind Code |
A1 |
Laronde; Frank ; et
al. |
February 11, 2010 |
COVALENTLY GRAFTED PHARMACEUTICALLY ACTIVE POLYMERS
Abstract
The invention relates to graftable polymers comprising
biologically active agents and the use of such polymers in the
manufacture of shaped articles, such as implantable medical devices
and catheters. The graftable polymers are covalently grafted to a
surface via one or more grafting moieties incorporated into the
pharmaceutically-active graftable polymer. The coated articles of
the invention can further comprise tie-coats, and the ratio of
polymer:tie coat can be used to adjust the rate of drug
elution.
Inventors: |
Laronde; Frank; (Toronto,
CA) ; Gu; Fan; (Mississauga, CA) |
Correspondence
Address: |
CLARK & ELBING LLP
101 FEDERAL STREET
BOSTON
MA
02110
US
|
Assignee: |
Interface Biologics, Inc.
Toronto
CA
|
Family ID: |
41216380 |
Appl. No.: |
12/429703 |
Filed: |
April 24, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61125459 |
Apr 25, 2008 |
|
|
|
Current U.S.
Class: |
424/423 ;
424/78.17; 528/26 |
Current CPC
Class: |
C08G 18/61 20130101;
A61L 15/46 20130101; A61L 29/10 20130101; C08G 18/12 20130101; C08G
18/73 20130101; A61L 27/54 20130101; C08G 18/38 20130101; C08G
18/4277 20130101; A61L 2300/406 20130101; A61P 31/00 20180101; C08G
18/12 20130101; C08G 18/12 20130101; A61L 29/16 20130101; A61L
31/16 20130101; A61K 31/496 20130101; A61K 47/58 20170801; A61K
47/59 20170801; A61L 27/34 20130101; A61L 31/10 20130101; C08G
18/384 20130101; C08G 18/3802 20130101 |
Class at
Publication: |
424/423 ; 528/26;
424/78.17 |
International
Class: |
A61K 9/00 20060101
A61K009/00; C08G 77/388 20060101 C08G077/388; A61K 31/765 20060101
A61K031/765; A61P 43/00 20060101 A61P043/00; A61P 31/00 20060101
A61P031/00 |
Claims
1. A graftable polymer comprising (i) subunits that comprise one or
more biologically active agents; (ii) an oligomeric segment; and
(iii) a grafting moiety capable of forming a covalent bond with a
surface, wherein said graftable polymer has a molecular weight
between 14 Kda and 2000 Kda, and said graftable polymer has a
structure according to any of Formulas (I)-(IV), wherein (A)
Formula (I) has the following structure:
C1-[Bio-(C1-{Oligo-G'}).sub.o-].sub.p (I) wherein (i) each Bio is,
independently, one or more biologically active agents or precursors
thereof; (ii) C1 is a coupling segment linking Bio to Oligo; (iii)
Oligo comprises a repeating monomeric unit or units that number
less than 50 monomeric units, and has a molecular weight less than
5 KDa; (iv) G' comprises a grafting moiety that is located along
the main chain of the graftable polymer; wherein each of o and p
is, independently, an integer greater than 0; (B) Formula (II) has
the following structure ##STR00033## wherein (i) each Bio is,
independently, one or more biologically active agents or precursors
thereof; (ii) C1 is a coupling segment linking Bio to Oligo; (iii)
Oligo comprises a repeating monomeric unit or units that number
less than 50 monomeric units and has a molecular weight less than 5
KDa; (iv) G'' comprises a grafting moiety that is pendant from the
main chain of the graftable polymer; wherein each of o and p is,
independently, an integer greater than 0, and. wherein G'' is
optionally covalently tethered to Bio, C.sub.1, or Oligo; (C)
Formula (III) has the following structure:
C.sub.1-[(Bio-C2-Bio).sub.n-(C1-{Oligo-G'}).sub.o-].sub.p (III)
wherein (i) each Bio is, independently, one or more biologically
active agents or precursors thereof; (ii) C1 is a coupling segment
linking Bio to Oligo; (iii) C2 is a hydrolysable coupling segment
or a polyamide linker susceptible to hydrolysis by a peptidase
enzyme linking Bio to Bio; (iv) Oligo comprises a repeating
monomeric unit or units that number less than 5 monomeric units and
has a molecular weight less than 5 KDa; (v) G' comprises a grafting
moiety that is located along the main chain of the graftable
polymer; wherein each of n, o, and p is independently an integer
greater than 0; and (D) Formula (IV) has the following structure:
##STR00034## wherein (i) each Bio is, independently, one or more
biologically active agents or precursors thereof; (ii) C1 is a
coupling segment linking Bio to Oligo; (iii) C2 is a hydrolysable
coupling segment or a polyamide linker susceptible to hydrolysis by
a peptidase enzyme linking Bio to Bio; (iv) Oligo comprises a
repeating monomeric unit or units that number less than 50
monomeric units and has a molecular weight less than 5 KDa; (v) G''
comprises a grafting moiety that is pendant from the main chain of
the graftable polymer; wherein each of n, o, and p is independently
an integer greater than 0, and wherein G'' is optionally covalently
tethered to Bio, C1, C2, or Oligo.
2. The graftable polymer of claim 1, wherein Bio comprises
ciprofloxacin or chhlorhexidine.
3. The graftable polymer of claim 1, wherein the grafting moiety
comprises an electrophile, a nucleophile, a component of a
cycloaddition reaction, or a component of a coupling reaction.
4. The graftable polymer of claim 1, wherein G' comprises a
grafting moiety that is an activated silicon center or a
hydridosilane.
5. The graftable polymer of claim 4, wherein G' is selected from:
##STR00035## wherein, independently, (i) R.sub.1 is selected from
--CH.sub.3, --OCH.sub.3, or --OCH.sub.2CH.sub.3; (ii) R.sub.2,
R.sub.3, R.sub.4, and R.sub.5 are selected from --OCH.sub.3 or
--OCH.sub.2CH.sub.3; (iii) m is an integer between 1 and 5; and
(iv) n is an integer greater than 0; or ##STR00036## wherein,
independently, (i) R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are
selected from --OCH.sub.3 or --OCH.sub.2CH.sub.3; (ii) R.sub.5 is
selected from --(CH.sub.2).sub.p-- or --(CH.sub.2).sub.pO--; (iii)
m is an integer between 1-5; (iv) n is an integer greater than 0;
and (v) p is an integer between 0-6; or ##STR00037## wherein,
independently, m and n are integers between 1-6.
6. The graftable polymer of claim 5, wherein R.sub.1 is
--OCH.sub.2CH.sub.3, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are
--OCH.sub.2CH.sub.3, and m=3 in (a); R.sub.1, R.sub.2, R.sub.3, and
R.sub.4 are --OCH.sub.2CH.sub.3, R.sub.5 is --(CH.sub.2).sub.2O--,
and m is 1 in (b); or. m is 3 and n is 1 in (c).
7. The graftable polymer of claim 1, wherein G'' is ##STR00038##
wherein, independently (i) X is either --NH-- or --O--; (ii) m is
an integer between 1 and 6; (iii) n is an integer between 0 and 6;
and (iv) R is an optional substituent selected from --H;
--NO.sub.2, or --CF.sub.3.
8. The graftable polymer of claim 7, wherein G'' is
##STR00039##
9. The graftable polymer of claim 8, wherein Bio is ciprofloxacin
or chlorhexidine; C1 comprises 2,2,4-trimethylhexamethylene
diisocyanate (THDI); Oligo comprises poly(.epsilon.-caprolactone)
diol (PCL); and ##STR00040##
10. An article having a surface comprising a pharmaceutically
active polymer covalently tethered thereto, said pharmaceutically
active polymer comprising (i) subunits that comprise one or more
biologically active agents; (ii) an oligomeric segment; and (iii)
at least one covalent bond to said surface, wherein said
pharmaceutically active polymer has a molecular weight between 14
Kda and 2000 Kda, and said pharmaceutically active polymer has a
structure according to any of Formulas (V)-(VIII), wherein (A)
Formula (V) has the following structure:
C1-[Bio-(C1-{Oligo-G'}).sub.o-].sub.p (V), wherein (i) each Bio is,
independently, one or more biologically active agents or precursors
thereof; (ii) C1 is a coupling segment linking Bio to Oligo; (iii)
Oligo comprises a repeating monomeric unit or units that number
less than 50 monomeric units and with molecular weights less than 5
KDa; (iv) G' comprises a grafted moiety that is located along the
main chain of said pharmaceutically active polymer and covalently
tethered to said surface; wherein each of o and p is,
independently, an integer greater than 0; (B) Formula (VI) has the
following structure: ##STR00041## wherein (i) each Bio is,
independently, one or more biologically active agents or precursors
thereof; (ii) C1 is a coupling segment linking Bio to Oligo; (iii)
Oligo comprises a repeating monomeric unit or units that number
less than 50 monomeric units and with molecular weights less than 5
KDa; (iv) G'' comprises a grafted moiety that is pendant from the
main chain of said pharmaceutically active polymer and covalently
tethered to said surface; wherein each of o and p is,
independently, an integer greater than 0; (C) Formula (VII) has the
following structure:
C1-[(Bio-C2-Bio).sub.n-(C1-{Oligo-G'}).sub.o-].sub.p (VII) wherein
(i) each Bio is, independently, one or more biologically active
agents or precursors thereof; (ii) C1 is a coupling segment linking
Bio to Oligo; (iii) C2 is a hydrolysable coupling segment or a
polyamide linker susceptible to hydrolysis by a peptidase enzyme
linking Bio to Bio; (iv) Oligo comprises a repeating monomeric unit
or units that number less than 50 monomeric units and with
molecular weights less than 5 KDa; (v) G' comprises a grafted
moiety that is located along the main chain of said
pharmaceutically active polymer and covalently tethered to said
surface; wherein each of n, o, and p is independently an integer
greater than 0; and (D) Formula (VIII) has the following structure:
##STR00042## wherein (i) each Bio is, independently, one or more
biologically active agents or precursors thereof; (ii) C1 is a
coupling segment linking Bio to Oligo; (iii) C2 is a hydrolysable
coupling segment or a polyamide linker susceptible to hydrolysis by
a peptidase enzyme linking Bio to Bio; (iv) Oligo comprises a
repeating monomeric unit or units that number less than 50
monomeric units and with molecular weights less than 5 KDa; (v) G''
comprises a grafted moiety that is pendant from the main chain of
said pharmaceutically active polymer and covalently tethered to
said surface; wherein each of n, o, and p is independently an
integer greater than 0; and wherein G'' is optionally covalently
tethered to Bio, C1, C2, or Oligo.
11. The article of claim 10, wherein Bio comprises an
anti-microbial.
12. The article of claim 11, wherein the anti-microbial is
ciprofloxacin or chlorhexidine.
13. The article of claim 10, wherein G' comprises a grafted moiety
formed by reaction of an activated silicon center with a
nucleophile.
14. The article of claim 13, wherein G' is ##STR00043## wherein,
independently, (i) R is selected from --CH.sub.3, --OCH.sub.3, or
--OCH.sub.2CH.sub.3; (ii) R.sub.2, R.sub.3, R.sub.4, and R.sub.5
are selected from --OCH.sub.3, --OCH.sub.2CH.sub.3, or a covalent
bond to the base or base polymer wherein at least one of R.sub.2,
R.sub.3, R.sub.4, or R.sub.5 is a covalent bond to the base
polymer; (iii) m is an integer between 1 and 5; and (iv) n is an
integer greater than 0.
15. The article of claim 14, wherein (i) R.sub.1 is
--OCH.sub.2CH.sub.3; (ii) R.sub.2, R.sub.3, R.sub.4, and R.sub.5
are selected, independently, from --OCH.sub.3, --OCH.sub.2CH.sub.3,
or a covalent bond to the base or base polymer wherein at least one
of R.sub.2, R.sub.3, R.sub.4, or R.sub.5 is a covalent bond to the
base or base polymer; (iii) m is 3; and (iv) n is an integer
greater than 0.
16. The article of claim 14, wherein said surface comprises a
ceramic or a base polymer that comprises polysilicones,
polyurethanes, latex, polyethyleneterephthalate, or
polyvinylchloride.
17. The article of claim 16, wherein said base polymer comprises
polysilicone.
18. The article of claim 10, wherein G' comprises a grafted moiety
formed by reaction of a nitrene precursor or a component of a
cycloaddition reaction.
19. The article of claim 18, wherein G' is ##STR00044## wherein,
independently (i) X is either --NH-- or --O--; (ii) m is an integer
between 1 and 6; (iii) n is an integer between 0 and 6; (iv)
R.sub.1 and R.sub.2 are, independently, H or a covalent bond to the
base or base polymer, wherein at least one of R.sub.1 and R.sub.2
is a covalent bond to the base or base polymer; and (v) R.sub.3 is
an optional substituent selected from --H; --NO.sub.2, or
--CF.sub.3.
20. The article of claim 19, wherein X is --O--; m is 2; n is 5;
Bio is ciprofloxacin or chlorhexidine; C1 comprises
2,2,4-trimethylhexamethylene diisocyanate (THDI); and Oligo
comprises poly(.epsilon.-caprolactone) diol (PCL).
21. The article of claim 19, wherein said surface comprises a metal
or an alloy thereof, a ceramic or a base polymer, and wherein said
base polymer comprises polysilicones, polyurethanes, latex,
polyethyleneterephthalate, or polyvinylchloride.
22. The article of claim 10, wherein said article is an implantable
medical device, self-supporting film, or fiber.
23. The article of claim 22, wherein said article is an implantable
medical device selected from a cardiac-assist device, a catheter, a
stent, a prosthetic implant, a suture, a cuff, a mesh, a hernia
patch, a wound dressing, a bandage, an artificial sphincter, and a
drug delivery device.
24. The article of claim 23, wherein the implantable medical device
is a catheter.
25. The article of claim 22, wherein said article comprises a
polysilicone surface, polyurethane surface, latex surface,
polyvinylchloride surface, ceramic surface, or a metallic surface,
and wherein said surface comprises a pharmaceutically active
polymer covalently tethered thereto.
26. The article of claim 22, wherein said article comprises a
surface that comprises at least two different pharmaceutically
active agents.
27. The article of claim 26, wherein said pharmaceutically active
agents are a membrane active biocide and a fluoroquinolone.
28. The article of claim 27, wherein the membrane active biocide is
chlorhexidine and the fluoroquinolone is ciprofloxacin.
29. The article of claim 10, wherein said article further comprises
tie-coats.
30. The article of claim 29, wherein said tie-coat was applied
separately from the pharmaceutically active polymer.
31. The article of claim 29, wherein said tie-coat was applied to
the surface as part of a mixture comprising the pharmaceutically
active polymer.
32. The article of claim 29, wherein the weight to weight ratio of
the pharmaceutically active polymer:tie coat ranges from 1:2 to
50:1.
33. The article of claim 32, wherein the weight to weight ratio of
the pharmaceutically active polymer:tie coat is 2:1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit from U.S. Provisional
Application No. 61/125,459, filed Apr. 25, 2008, hereby
incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The invention features graftable polymers including
biologically active agents and the use of such polymers in the
manufacture of shaped articles.
[0003] Polymeric materials have been widely used for manufacturing
of medical devices such as artificial organs, implants, medical
devices, vascular prostheses, blood pumps, artificial kidney, heart
valves, pacemaker lead wire insulation, intra-aortic balloon,
artificial hearts, dialyzers and plasma separators, among others.
The polymer used within a medical device must be biocompatible
(e.g., must not produce toxic, allergic, inflammatory reactions, or
other adverse reactions). It is the physical, chemical and
biological processes at the interface, between the biological
system and the synthetic materials used, which defines the short-
and long-term potential applications of a particular device. In
general, the exact profile of biocompatibility and biodegradation,
including chemical and physical/mechanical properties i.e.,
elasticity, stress, ductility, toughness, time dependent
deformation, strength, fatigue, hardness, wear resistance, and
transparency for a biomaterial are extremely variable.
[0004] The polymeric coating of a medical device may also serve as
a repository for delivery of a biologically active agent. Where the
active agent is a pharmaceutical drug, it is often desirable to
release the drug from the medical device over an extended period of
time. Most systems for kinetically controlled direct drug delivery
employ a polymer. For example, the agent may be released as the
polymer enzymatically degrades or disintegrates in the body or may
diffuse out of the polymeric matrix at a controlled rate. A
site-specific drug transfer system can produce a high concentration
of agent at the treatment site, while minimizing the adverse
effects associated with systemic administration.
[0005] In order to maintain the effectiveness of the polymeric
coating, non-productive surface degradation or erosion should be
minimized such that sufficient quantities of the drug-releasing
polymer remain available for the required duration of
pharmaceutical activity. One representative pathway of surface
erosion is the flaking of the surface of a blended polymer. The use
of excess amounts of a pharmaceutically active polymer is one means
by which sufficient quantities of drug may be ensured. The
administration of excess amount of drug and drug-containing
polymer, however, may lead to the release of drug beyond an optimal
time frame. Such outcomes may lead to undesirable side effects in
patients. In the manufacture of shaped articles using blends of
base polymers with polymers that include biologically active
agents, reducing the proportion of the base polymer in order to
accommodate increased amounts of pharmaceutically active polymers
may adversely affect the mechanical properties of the shaped
article. As a result, there is a need for pharmaceutically active
polymers, polymer surfaces, shaped articles, and implantable
medical devices with increased longevity that will maintain
pharmaceutical efficacy for the desired time period as well as
retain the desirable properties of the base polymer.
SUMMARY OF THE INVENTION
[0006] The invention features graftable polymers including
biologically active agents and the use of such polymers in the
manufacture of shaped articles, such as implantable medical devices
and catheters. The graftable polymers are covalently grafted to a
surface via one or more grafting moieties incorporated into the
pharmaceutically-active graftable polymer. These polymers show
pharmaceutical efficacy while reducing possible adverse side
effects in patients or mechanical defects in the device that result
from high concentrations of the pharmaceutically active agent.
[0007] Accordingly, in a first aspect the invention features a
graftable polymer including subunits that include one or more
biologically active agents; an oligomeric segment; and a grafting
moiety capable of forming a covalent bond with a surface, with the
graftable polymer having a molecular weight between 14 KDa and 2000
KDa. The molecular weight of any of the graftable polymers of the
invention may also be between 14-50 KDa, 14-100 KDa, 14-200 KDa,
25-200 KDa, 50-200 KDa, 50-190 KDa, 50-180 KDa, 50-170 KDa, 50-160
KDa, 50-150 KDa, 50-140 KDa, 50-130 KDa, 50-120 KDa, 50-100 KDa,
50-90 KDa, 50-90 KDa, 50-80 KDa, 50-70 KDa, 50-60 KDa, 14-300 KDa,
14-400 KDa, 14-500 KDa, 14-600 KDa, 14-700 KDa, 14-800 KDa, 14-900
KDa, or 14-1000 KDa.
[0008] In certain embodiments, the graftable polymer is described
by Formula (I)
C1-[Bio-(C1-{Oligo-G'}).sub.o--].sub.p (I)
[0009] In Formula (I) each Bio is, independently, one or more
biologically active agents or precursors thereof; C1 is a coupling
segment linking Bio to Oligo; Oligo includes a repeating monomeric
unit or units that number less than 50 monomeric units and has a
molecular weight less than 5 KDa; G' includes a grafting moiety
that is located along the main chain of the graftable polymer; and
each of o and p is, independently, an integer greater than 0 but
less than 150. Oligo may number less than 50, 45, 40, 35, 30, 25,
20, 15, 10, or even less than 5. Each of o and p may also be any
integer between 1-5, 1-10, 1-15, 1-20, 1-25, 1-30, 1-35, 1-40,
1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95,
1-100, 1-105, 1-110, 1-115, 1-120, 1-125, 1-130, 1-135, 1-140,
1-145, or 1-150.
[0010] In other embodiments, the graftable polymer is described by
Formula (II)
##STR00001##
In Formula (II) each Bio is, independently, one or more
biologically active agents or precursors thereof; C1 is a coupling
segment linking Bio to Oligo; Oligo includes a repeating monomeric
unit or units that number less than 50 monomeric units and has a
molecular weight less than 5 KDa; G'' includes a grafting moiety
that is pendant from the main chain of the graftable polymer; and
each of o and p is an integer greater than 0 but less than 150.
Oligo may number less than 50, 45, 40, 35, 30, 25, 20, 15, 10, or
even 5. Each of o and p may be, independently, any integer between
1-5, 1-10, 1-15, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55,
1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-105,
1-110, 1-115, 1-120, 1-125, 1-130, 1-135, 1-140, 1-145, or 1-150.
In certain embodiments, G'' is covalently tethered to Bio, C1, or
Oligo.
[0011] In other embodiments, the graftable polymer is described by
Formula (III)
C1-[(Bio-C2-Bio).sub.n-(C1-{Oligo-G'}).sub.o-].sub.p (III)
In Formula (III) each Bio is, independently, one or more
biologically active agents or precursors thereof; C1 is a coupling
segment linking Bio to Oligo; C2 is a hydrolysable coupling segment
or a polyamide linker susceptible to hydrolysis by a peptidase
enzyme linking Bio to Bio; Oligo includes a repeating monomeric
unit or units that number less than 50 monomeric units and has a
molecular weight less than 5 KDa; G' includes a grafting moiety
that is located along the main chain of the graftable polymer; and
each of n, o, and p is, independently, an integer greater than 0
but less than 150. Oligo may number less than 50, 45, 40, 35, 30,
25, 20, 15, 10, or even less than 5. Each of n, o, and p may also
be any integer between 1-5, 1-10, 1-15, 1-20, 1-25, 1-30, 1-35,
1-40, 1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90,
1-95, 1-100, 1-105, 1-110, 1-115, 1-120, 1-125, 1-130, 1-135,
1-140, 1-145, or 1-150.
[0012] In still other embodiments, the graftable polymer is
described by Formula (IV)
##STR00002##
In Formula (IV), each Bio is, independently, one or more
biologically active agents or precursors thereof; C1 is a coupling
segment linking Bio to Oligo; C2 is a hydrolysable coupling segment
or a polyamide linker susceptible to hydrolysis by a peptidase
enzyme linking Bio to Bio; Oligo includes a repeating monomeric
unit or units that number less than 50 monomeric units and has a
molecular weight less than 5 KDa; G'' includes a grafting moiety
that is pendant from the main chain of the graftable polymer; and
each of n, o, and p is, independently, an integer greater than 0
and less than 150. Oligo may number less than 50, 45, 40, 35, 30,
25, 20, 15, 10, or even less than 5. Each of n, o, and p may also
be any integer between 1-5, 1-10, 1-15, 1-20, 1-25, 1-30, 1-35,
1-40, 1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90,
1-95, 1-100, 1-105, 1-110, 1-115, 1-120, 1-125, 1-130, 1-135,
1-140, 1-145, or 1-150. In certain embodiments, G'' is covalently
tethered to Bio, C1, C2, or Oligo.
[0013] In certain embodiments, the graftable polymer of Formula
(II) or (III) includes G', which includes a grafting moiety that
includes an electrophile, a nucleophile, a component of a
cycloaddition reaction, or a component of a coupling reaction.
[0014] Electrophiles that can be used in the polymers and articles
of the invention include, without limitation, activated silicon
centers. For example, G' can be described by the formula
##STR00003##
wherein, independently, R.sub.1 is selected from --C.sub.1-6 alkyl
or --OC.sub.1-6 alkyl; each R.sub.2, R.sub.3, R.sub.4, and R.sub.5
is --OC.sub.1-6 alkyl; m is an integer between 1 and 5; and n is an
integer greater than 0 and less than 250. In some embodiments, m is
1, 2, 3, 4, or 5 and n is greater than 0 and less than 100, 95, 90,
85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or
even less than 5. In some embodiments, R.sub.1 is --CH.sub.3,
--OCH.sub.3, or --OCH.sub.2CH.sub.3 and R.sub.2, R.sub.3, R.sub.4,
and R.sub.5 are selected from --OCH.sub.3 or --OCH.sub.2CH.sub.3.
In certain embodiments, R.sub.1 is --OCH.sub.2CH.sub.3; R.sub.2,
R.sub.3, R.sub.4, and R.sub.5 are --OCH.sub.2CH.sub.3; and m 3.
[0015] Alternatively, G' can be described by the formula
##STR00004##
wherein, independently: R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are
selected from --OC.sub.1-6 alkyl; R.sub.5 is selected from
--(CH.sub.2).sub.p-- or --(CH.sub.2).sub.pO--; m is an integer
between 1-5; n is an integer greater than 0 and less than 250; and
p is an integer between 0-6. In some embodiments, m is 1, 2, 3, 4,
or 5; n is greater than 0 and less than 100, 95, 90, 85, 80, 75,
70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or even less
than 5; and p is 0, 1, 2, 3, 4, 5, or 6. In other embodiments,
R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are selected from
--OCH.sub.3 or --OCH.sub.2CH.sub.3. In certain embodiments,
R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are --OCH.sub.2CH.sub.3;
R.sub.5 is --(CH.sub.2).sub.2O--; and m is 1.
[0016] In other embodiments, the graftable polymer of Formula (II)
or (III) includes G', which includes a grafting moiety that
includes a component of a coupling reaction. In still other
embodiments, G' includes a grafting moiety that includes a
hydridosilane. In certain embodiments, G' is
##STR00005##
wherein, independently, m and n are integers between 1-6. In some
embodiments,
[0017] each m and n is, independently, 1, 2, 3, 4, 5, or 6. In
certain embodiments, m is 3 and n is 1.
[0018] In some embodiments, the graftable polymer of any of
Formulas (I), (II), (III), and (IV) includes G'' which includes a
grafting moiety that includes an electrophile, a nucleophile, a
component of a cycloaddition reaction, or a component of a coupling
reaction.
[0019] In other embodiments, G'' includes an electrophile or a
component of a cycloaddition reaction. In some embodiments, G''
is
##STR00006##
wherein, independently, X is either --NH-- or --O--; m is an
integer between 1 and 6; n is an integer between 0 and 6; and R is
an optional substituent selected from --H; --NO.sub.2, or
--CF.sub.3. In some embodiments, each m is, independently, 1, 2, 3,
4, 5, or 6 and n is 0, 1, 2, 3, 4, 5, or 6. For example, G'' can
include an electrophile and be selected from
##STR00007##
[0020] In certain embodiments,
[0021] Bio is ciprofloxacin or chlorhexidine;
[0022] C1 comprises 2,2,4-trimethylhexamethylene diisocyanate
(THDI);
[0023] Oligo comprises poly(.epsilon.-caprolactone) diol (PCL);
and
[0024] G'' is
##STR00008##
[0025] In some embodiments of the invention, the total weight of
all G' or G'' is 0.5-50% of the molecular weight of the graftable,
pharmaceutically active polymer. The total weight of G' or G''
relative to the molecular weight of the graftable, pharmaceutically
active polymer may also be 0.5-5%, 0.5-10%, 0.5-15%, 0.5-20%,
0.5-25%, 0.5-30%, 0.5-35%, 0.5-40%, 0.5-45%, 1-10%, 1-9%, 1-8%,
1-7%, 1-6%, 1-5%, 1-4%, 1-3%, 1-2%, 2-10%, 2-9%, 2-8%, 2-7%, 2-6%,
2-5%, 2-4%, 2-3%, 3-10%, 3-9%, 3-8%, 3-7%, 3-6%, 3-5%, or 3-4%.
[0026] Another aspect of the invention features an article having a
surface covalently tethered to a pharmaceutically active polymer
and the pharmaceutically active polymer includes subunits that
include one or more biologically active agents; an oligomeric
segment; and at least one covalent bond to the surface, wherein the
pharmaceutically active polymer has a molecular weight between 14
Kda and 2000 Kda. The molecular weight of the pharmaceutically
active polymer may also be between 14-50 KDa, 14-100 KDa, 14-200
KDa, 25-200 KDa, 50-200 KDa, 50-190 KDa, 50-180 KDa, 50-170 KDa,
50-160 KDa, 50-150 KDa, 50-140 KDa, 50-130 KDa, 50-120 KDa, 50-100
KDa, 50-90 KDa, 50-90 KDa, 50-80 KDa, 50-70 KDa, 50-60 KDa, 14-300
KDa, 14-400 KDa, 14-500 KDa, 14-600 KDa, 14-700 KDa, 14-800 KDa,
14-900 KDa, or 14-1000 KDa.
[0027] In some embodiments, the pharmaceutically active polymer is
described by Formula (V)
C1-[Bio-(C1-{Oligo-G'}).sub.o-].sub.p (V)
In Formula (V) each Bio is, independently, one or more biologically
active agents or precursors thereof; C1 is a coupling segment
linking Bio to Oligo; Oligo includes a repeating monomeric unit or
units that number less than 50 monomeric units and with molecular
weights less than 5 KDa; G' includes a grafted moiety that is
located along the main chain of the pharmaceutically active polymer
and covalently tethered to the surface; and each of o and p is,
independently, an integer greater than 0 and less than 150. Oligo
may number less than 50, 45, 40, 35, 30, 25, 20, 15, 10, or even
less than 5. Each of o and p may also be any integer between 1-5,
1-10, 1-15, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1-60,
1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-105, 1-110,
1-115, 1-120, 1-125, 1-130, 1-135, 1-140, 1-145, or 1-150.
[0028] In other embodiments, the pharmaceutically active polymer is
described by Formula (VI)
##STR00009##
[0029] In Formula (VI) each Bio is, independently, one or more
biologically active agents or precursors thereof; C1 is a coupling
segment linking Bio to Oligo; Oligo includes a repeating monomeric
unit or units that number less than 50 monomeric units and with
molecular weights less than 5 KDa; G'' includes a grafted moiety
that is pendant from the main chain of the pharmaceutically active
polymer and covalently tethered to the surface; and each of o and p
is, independently, an integer greater than 0 and less than 150.
Oligo may number less than 50, 45, 40, 35, 30, 25, 20, 15, 10, or
even less than 5. Each of o and p may also be, independently, any
integer between 1-5, 1-10, 1-15, 1-20, 1-25, 1-30, 1-35, 1-40,
1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95,
1-100, 1-105, 1-110, 1-115, 1-120, 1-125, 1-130, 1-135, 1-140,
1-145, or 1-150. In other embodiments, G'' is covalently tethered
to Bio, C1, or Oligo.
[0030] In other embodiments, the pharmaceutically active polymer is
described by Formula (VII)
C1-[(Bio-C2-Bio).sub.n-(C1-{Oligo-G'}).sub.o-].sub.p (VII)
In Formula (VII) each Bio is, independently, one or more
biologically active agents or precursors thereof; C1 is a coupling
segment linking Bio to Oligo; C2 is a hydrolysable coupling segment
or a polyamide linker susceptible to hydrolysis by a peptidase
enzyme linking Bio to Bio; Oligo includes a repeating monomeric
unit or units that number less than 50 monomeric units and with
molecular weights less than 5 KDa; G' includes a grafted moiety
that is located along the main chain of the pharmaceutically active
polymer and covalently tethered to the surface; and each of n, o,
and p is independently an integer greater than 0 and less than 150.
Oligo may number less than 50, 45, 40, 35, 30, 25, 20, 15, 10, or
even less than 5. Each of n, o, and p may also be, independently,
any integer between 1-5, 1-10, 1-15, 1-20, 1-25, 1-30, 1-35, 1-40,
1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95,
1-100, 1-105, 1-110, 1-115, 1-120, 1-125, 1-130, 1-135, 1-140,
1-145, or 1-150.
[0031] In still other embodiments, the pharmaceutically active
polymer is described by Formula (VIII)
##STR00010##
In Formula (VIII) each Bio is, independently, one or more
biologically active agents or precursors thereof; C1 is a coupling
segment linking Bio to Oligo; C2 is a hydrolysable coupling segment
or a polyamide linker susceptible to hydrolysis by a peptidase
enzyme linking Bio to Bio; Oligo includes a repeating monomeric
unit or units that number less than 50 monomeric units and with
molecular weights less than 5 KDa; G'' includes a grafted moiety
that is pendant from the main chain of the pharmaceutically active
polymer and covalently tethered to the surface; and each of n, o,
and p is independently an integer greater than 0 and less than 150.
Oligo may number less than 50, 45, 40, 35, 30, 25, 20, 15, 10, or
even less than 5. Each of n, o, and p may also be, independently,
any integer between 1-5, 1-10, 1-15, 1-20, 1-25, 1-30, 1-35, 1-40,
1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95,
1-100, 1-105, 1-110, 1-115, 1-120, 1-125, 1-130, 1-135, 1-140,
1-145, or 1-150. In further embodiments, G'' is covalently tethered
to Bio, C1, C2, or Oligo.
[0032] In other embodiments, the pharmaceutically active polymer of
Formula (VI) or (VII) includes G' which includes a grafted moiety
formed by reaction of an activated silicon center with a
nucleophile.
[0033] In still other embodiments, G' is
##STR00011##
wherein, independently, R.sub.1 is selected from --C.sub.1-6 alkyl
or --OC.sub.1-6 alkyl; each R.sub.2, R.sub.3, R.sub.4, and R.sub.5
is --OC.sub.1-6 alkyl or a covalent bond to the base or base
polymer, wherein at least one of R.sub.2, R.sub.3, R.sub.4, or
R.sub.5 is a covalent bond to the base polymer; m is an integer
between 1 and 5; and n is an integer greater than 0 and less than
250. In some embodiments, m is 1, 2, 3, 4, or 5 and n is greater
than 0 and less than 250, 225, 200, 175, 150, 125, 100, 75, 50, 25,
10, or even less than 5. In other embodiments, R.sub.1 is
--CH.sub.3, --OCH.sub.3, or --OCH.sub.2CH.sub.3; and R.sub.2,
R.sub.3, R.sub.4, and R.sub.5 are selected from --OCH.sub.3,
--OCH.sub.2CH.sub.3, or a covalent bond to the base or base
polymer, wherein at least one of R.sub.2, R.sub.3, R.sub.4, or
R.sub.5 is a covalent bond to the base polymer. In further
embodiments, R.sub.1 is --OCH.sub.2CH.sub.3; R.sub.2, R.sub.3,
R.sub.4, and R.sub.5 are selected, independently, from --OCH.sub.3,
--OCH.sub.2CH.sub.3, or a covalent bond to the base or base polymer
wherein at least one of R.sub.2, R.sub.3, R.sub.4, or R.sub.5 is a
covalent bond to the base or base polymer; m is 3; and n is an
integer greater than 0.
[0034] In some embodiments, Bio includes an anti-microbial. In
further embodiments, the anti-microbial is ciprofloxacin or
chlorhexidine.
[0035] In some embodiments, the surface is a base polymer. In some
embodiments, the base polymer includes polysilicones,
polyurethanes, latex, polyethyleneterephthalate, or
polyvinylchloride.
[0036] In other embodiments, the base polymer further comprises tie
coats (e.g., tert-butyloxy triacetoxysilane, ethyl
triacetoxysilane, methyl triacetoxysilane, the tie coats described
in Scheme 1 or Table 1, or any combination thereof). In certain
embodiments, the tie-coat is applied separately from the graftable
or pharmaceutically active polymer. In other embodiments, tie-coat
is applied to the surface as part of a mixture comprising the
pharmaceutically active polymer or the graftable polymer. In other
embodiments, the weight to weight (w/w) ratio of the
pharmaceutically active or graftable polymer:tie coat ranges from
1:10 to 50:1 (e.g., the ratio may be 1:2, 1:1, 2:1, 3:1, 4:1, 5:1,
10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, or 50:1). In
certain embodiments, the w/w ratio of the pharmaceutically active
or graftable polymer:tie coat is 1:2, 1: 1, or 2:1. In other
embodiments, the w/w ratio of the pharmaceutically active or
graftable polymer:tie coat ranges from 1:2 to 50:1. In other
embodiments, the w/w ratio of the polymer:tie coat ranges from
[0037] (A) 1:10 to 1:1 (e.g., 1:9-1:1; 1:8-1:1; 1:7-1:1; 1:6-1:1;
1:5-1:1; 1:4-1:1; 1:3-1:1; or 1:2-1:1); [0038] (B) 1:1-20:1 (e.g.,
1:1-2:1; 1:1-3:1; 1:1-4:1; 1:1-5:1; 1:1-6:1; 1:1-7:1; 1:1-8:1;
1:1-9:1; 1:1-10:1; 1-15:1; 1-20:1; 2:1-3:1; 2:1-4:1; 2:1-5:1;
2:1-6:1; 2:1-7:1; 2:1-8:1; 2:1-9:1; 2:1-10:1; 2:1-15:1; 2:1-20:1;
5:1-7.5:1; 5:1-10:1; 5:1-15:1; 5:1-20:1; 10:1-15:1; 10:1-20:1; or
15:1-20:1); or [0039] (C) 20:1-50:1 (e.g., 20:1-25:1; 20:1-30:1;
20:1-35:1; 20:1-40:1; 20:1-45:1; 20:1-50:1; 30:1-40:1; 30:1-50:1;
or 40:1-50:1). In some embodiments, the w/w ratio of the
polymer:tie coat is used to adjust the rate of elution of the drug
(e.g., the w/w ratio of (A) is used to slow the rate of elution of
a drug or the w/w ratio of (B) or (C) is used to increase the rate
of elution of a drug.
[0040] In some embodiments, the surface includes a ceramic. In
certain embodiments, the ceramic is titanium dioxide.
[0041] In other embodiments, G' includes
##STR00012##
wherein, independently, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are
selected from --OC.sub.1-6 alkyl or a covalent bond to the base or
base polymer, wherein at least one of R.sub.1, R.sub.2, R.sub.3, or
R.sub.4 is a covalent bond to the base or base polymer; R.sub.5 is
selected from --(CH.sub.2).sub.p-- or --(CH.sub.2).sub.pO--; m is
an integer between 1-5; n is an integer greater than 0 and less
than 250; and p is an integer between 0-6. In some embodiments, m
is 1, 2, 3, 4, or 5; n is greater than 0 and less than 250, 225,
200, 175, 150, 125, 100, 75, 50, 25, 10, or even less than 5; and p
is 0, 1, 2, 3, 4, 5, or 6. In other embodiments, R.sub.1, R.sub.2,
R.sub.3, and R.sub.4 are selected from --OCH.sub.3,
--OCH.sub.2CH.sub.3, or a covalent bond to the base or base polymer
wherein at least one of R.sub.1, R.sub.2, R.sub.3, or R.sub.4 is a
covalent bond to the base or base polymer. In still other
embodiments: R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are selected,
independently, from --OCH.sub.2CH.sub.3 or a covalent bond to the
base or base polymer wherein at least one of R.sub.1, R.sub.2,
R.sub.3, or R.sub.4 is a covalent bond to the base or base polymer;
R.sub.5 is --(CH.sub.2).sub.pO--; m is 1; n is an integer greater
than 0 and less than 250; and p is 2.
[0042] In some embodiments, Bio includes an anti-microbial. In
certain embodiments, the anti-microbial is ciprofloxacin.
[0043] In other embodiments, the surface includes a base polymer In
certain embodiments, the base polymer includes polysilicones,
polyurethanes, latex, polyethyleneterephthalate, or
polyvinylchloride. In particular embodiments, the base polymer
includes polysilicone.
[0044] In other embodiments, the surface includes a ceramic. In
certain embodiments, the ceramic is titanium dioxide.
[0045] In still other embodiments, the pharmaceutically active
polymer of Formulas (V) and (VII) include G' which includes a
grafted moiety formed by reaction of a nitrene precursor or a
component of a cycloaddition reaction.
[0046] In some embodiments, the pharmaceutically active polymer
includes the grafted moiety G' that is
##STR00013##
wherein, independently, X is either --NH-- or --O--; m is an
integer between 1 and 6;
[0047] n is an integer between 0 and 6; R.sub.1 and R.sub.2 are,
independently, H or a covalent bond to the base or base polymer,
wherein at least one of R.sub.1 and R.sub.2 is a covalent bond to
the base or base polymer; and R.sub.3 is an optional substituent
selected from --H, --NO.sub.2, or --CF.sub.3. In certain
embodiments, m is 1, 2, 3, 4, 5, or 6 and n is 0, 1, 2, 3, 4, 5, or
6. In further embodiments, X is --O--; m is 2; n is 5; Bio is
ciprofloxacin or chlorhexidine; C1 comprises
2,2,4-trimethylhexamethylene diisocyanate (THDI); and Oligo
comprises poly(.epsilon.-caprolactone) diol (PCL).
[0048] In other embodiments, Bio includes an anti-microbial. In
certain embodiments, the anti-microbial is ciprofloxacin.
[0049] In some embodiments, the surface includes a base polymer. In
certain embodiments, the base polymer includes polysilicones,
polyurethanes, latex, polyethyleneterephthalate, or
polyvinylchloride. In particular embodiments, the base polymer
includes polyurethane or polyvinylchloride.
[0050] In still other embodiments, the surface includes a ceramic.
In certain embodiments, the ceramic is titanium dioxide.
[0051] In some embodiments, the surface the includes a metal or an
alloy thereof. In certain embodiments, the metal or alloy thereof
is selected from aluminum, cadmium, chromium, cobalt, copper, gold,
iridium, iron, magnesium, molybdenum, nickel, palladium, platinum,
silver, titanium, zinc, cobalt/chromium alloys, silver alloys,
stainless steel, titanium alloys, and pyrolytic carbon.
[0052] In some embodiments of the invention, the total weight of
all G' or G'' is 0.5-50% of the molecular weight of the
pharmaceutically active polymer that is covalently grafted to the
surface of the article. The total weight of G' or G'' relative to
the molecular weight of the pharmaceutically active polymer may
also be 0.5-5%, 0.5-10%, 0.5-15%, 0.5-20%, 0.5-25%, 0.5-30%,
0.5-35%, 0.5-40%, 0.5-45%, 1-5%, 1-10%, 1-15%, 1-20%, 1-25%, 1-30%,
1-35%, 1-40%, 1-45%, 1-50%, 5-10%, 5-15%, 5-20%, 5-25%, 5-30%,
5-35%, 5-40%, 5-45%, or 5-50%.
[0053] In another aspect of the invention, the article of any of
the embodiments described herein is an implantable medical device,
self-supporting film, or fiber.
[0054] In some embodiments, the article is an implantable medical
device selected from a cardiac-assist device, a catheter, a stent,
a prosthetic implant, a suture, a cuff, a mesh, a hernia patch, a
wound dressing, a bandage, an artificial sphincter, and a drug
delivery device.
[0055] In certain embodiments, the implantable medical device is a
catheter.
[0056] In still other embodiments, the pharmaceutically active
polymer is tethered to an article including a ceramic surface, a
polysilicone surface, a polyurethane surface, a latex surface, a
metallic surface, or a polyvinylchloride surface.
[0057] In some embodiments, the article includes a surface that
includes at least two different pharmaceutically active agents. In
other embodiments, the two different pharmaceutically active agents
are a membrane active biocide and a fluoroquinolone. In certain
embodiments, the membrane active biocide is chlorhexidine and the
fluoroquinolone is ciprofloxacin.
[0058] In any of the polymers or articles described herein, the
biologically active agent may be an anti-inflammatory,
anti-oxidant, anti-coagulant, anti-microbial, cell receptor
ligands, bio-adhesive molecule, pesticide, bactericide, fungicide,
fragrance, or dye. In some embodiments, the biologically active
agent is an antimicrobial. In certain embodiments, the graftable
polymer includes two biologically active agents. In some
embodiments, the graftable polymer includes two
anti-microbials.
[0059] In any of the polymers or articles described herein, the
coupling segments C1 and C2 may be selected, independently, from:
ethylene glycol, butanediol, hexanediol, hexamethylenediol, 1,5
pentanediol, 2,2-dimethyl-1,3-propanediol, 1,4-cyclohexanediol,
1,4-cyclohexanedimethanol, tri(ethylene glycol), poly(ethylene
glycol), poly(ethylene oxide)diamine, lysine esters, siliconediols
and -diamines, polyetherdiols and -diamines, carbonatediols and
-diamines, dihydroxy vinyl derivatives, dihydroxy diphenylsulfone,
ethylenediamine, hexamethylenediamine, 1,2-diamino-2-methylpropane,
3,3-diamino-N-methyldipropylamine, 1,4 diaminobutane,
1,7-diaminoheptane, or 1,8-diaminooctane.
[0060] In any of the polymers or articles of the invention, Oligo
may number less than 50, 45, 40, 35, 30, 25, 20, 15, 10, or less
than 5 repeating monomeric units and may have a molecular weight of
less than 5 KDa, 4.5 KDa, 4 KDa, 3.5 KDa, 3 KDa, 2.5 KDa, 2 KDa,
1.5 KDa, 1 KDa, or even less than 0.5 KDa. Useful repeating
monomeric units include polyurethanes, polyureas, polyamides,
polyalkylene oxides, polycarbonates, polyesters, polylactones,
polysilicones, polyethersulfones, polyolefins, polyvinyls,
polypeptides, polysaccharides, or any combination thereof.
[0061] Anti-microbial agents useful in any of the polymers or
articles of the invention include: penicillin G, penicillin V,
methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin,
ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin,
piperacillin, azlocillin, temocillin, cepalothin, cephapirin,
cephradine, cephaloridine, cefazolin, cefamandole, cefuroxime,
cephalexin, cefprozil, cefaclor, loracarbef, cefoxitin,
cefmatozole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone,
ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir,
cefpirome, cefepime, chlorhexidine, BAL5788, BAL9141, imipenem,
ertapenem, meropenem, astreonam, clavulanate, sulbactam,
tazobactam, streptomycin, neomycin, kanamycin, paromycin,
gentamicin, tobramycin, amikacin, netilmicin, spectinomycin,
sisomicin, dibekalin, isepamicin, tetracycline, chlortetracycline,
demeclocycline, minocycline, oxytetracycline, methacycline,
doxycycline, erythromycin, azithromycin, clarithromycin,
telithromycin, ABT-773, lincomycin, clindamycin, vancomycin,
oritavancin, dalbavancin, teicoplanin, quinupristin and
dalfopristin, sulphanilamide, para-aminobenzoic acid, sulfadiazine,
sulfisoxazole, sulfamethoxazole, sulfathalidine, linezolid,
nalidixic acid, oxolinic acid, norfloxacin, perfloxacin, enoxacin,
ofloxacin, ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin,
grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin,
gatifloxacin, moxifloxacin, gemifloxacin, sitafloxacin,
metronidazole, daptomycin, garenoxacin, ramoplanin, faropenem,
polymyxin, tigecycline, AZD2563, and trimethoprim.
[0062] By "activated carbonyl" is meant a functional group
R.sup.1R.sup.2--C(O)R.sup.3 or R.sup.1--R.sup.2C(O)R.sup.3 wherein,
independently, R.sup.1 is a bond or an attachment to the graftable
monomer, graftable polymer, or surface; R.sup.2 is selected from H,
optionally substituted C.sub.1-12 alkyl, optionally substituted
arenes, optionally substituted C.sub.1-12 alkarenes, optionally
substituted heteroarenes, or optionally substituted C.sub.1-12
alkheteroarenes; and R.sup.3 is a C.sub.1-6 alkoxy group, OH, or
halide.
[0063] By "activated phosphorus center" is meant a grafting moiety
that includes a trivalent phosphorus (III) or a pentavalent
phosphorus (V) center wherein at least one of the substituents is a
C.sub.1-C.sub.6 alkoxy group. Desirably, the alkoxy group is
--OCH.sub.3 or --OCH.sub.2CH.sub.3.
[0064] By "activated silicon center" is meant a grafting moiety
that includes a tetrasubstituted silicon center wherein at least
one of the substituents is a C.sub.1-C.sub.6 alkoxy group.
Desirably, the alkoxy group is --OCH.sub.3 or
--OCH.sub.2CH.sub.3.
[0065] By "activated sulfur center" is meant a grafting moiety that
includes a tetravalent sulfur wherein at least one of the
substituents is a C.sub.1-C.sub.6 alkoxy group. Desirably, the
alkoxy group is --OCH.sub.3 or --OCH.sub.2CH.sub.3.
[0066] By "alkoxy" is meant a group having the structure --OR,
where R is an optionally substituted alkyl group as described
herein.
[0067] By "allyl" is meant a functional group that is an optionally
substituted straight chain or branched chain saturated hydrocarbon
group having 1 to 12 carbons, unless otherwise specified. For
example, a "C.sub.1-10 alkyl group" refers to alkyl groups ranging
from 1-10 carbons.
[0068] By "alkylamino group" is meant a functional group having the
structure R.sup.1R.sub.2NH wherein R.sup.1 is a bond or an
attachment to the graftable monomer, graftable polymer, or surface
and R.sub.2 is an optionally substituted C.sub.1-2 alkyl group.
[0069] By "alkarene" is meant is a functional group having the
structure R.sup.1--R.sub.2--Ar where wherein R.sup.1 is a bond or
an attachment to the graftable monomer, graftable polymer, or
surface, R.sub.2 is an optionally substituted C.sub.1-8 alkyl
group, and Ar is an arene.
[0070] By "alkheteroarene" is meant is a functional group having
the structure R.sup.1--R.sub.2--Het where wherein R.sup.1 is a bond
or an attachment to the graftable monomer, graftable polymer, or
surface, R.sub.2 is an optionally substituted C.sub.1-8 alkyl
group, and Het is a heteroarene.
[0071] By "alkene" is meant a functional group having the structure
R.sup.1R.sup.2C.dbd.CR.sup.3R.sup.4 wherein at least one of
R.sub.1, R.sub.2, R.sub.3, or R.sub.4 is a bond or an attachment to
the graftable monomer, graftable polymer, or a surface R.sup.1,
R.sup.2, R.sup.3, or R.sup.4 may be selected, independently, from
H, optionally substituted C.sub.1-12 alkyl, optionally substituted
arenes, or optionally substituted heteroarenes. Preferred alkenes
are those in which R.sup.1 is an attachment to the graftable
monomer and R.sup.2, R.sup.3, or R.sup.4 are H or C.sub.1-3
alkyl.
[0072] By "alkyl halide" is meant a functional group
R.sup.1R.sup.2CHR.sup.3--X wherein, independently, R.sup.1 is a
bond or an attachment to the graftable monomer, graftable polymer,
or surface; R.sup.2 is substituted C.sub.n alkyl where n=0-12; and
R.sup.3 is selected from H, optionally substituted C.sub.1-12
alkyl, optionally substituted arenes, optionally substituted
C.sub.1-12 alkarenes, optionally substituted heteroarenes, or
optionally substituted C.sub.1-12 alkheteroarene; and X is a
halogen.
[0073] By "alkyl psuedohalide" is meant a functional group
R.sup.1R.sup.2CHR.sup.3--X wherein, independently, R.sup.1 is a
bond or an attachment to the graftable monomer, graftable polymer,
or surface; R is substituted C.sub.n alkyl where n=0-12; and
R.sup.3 is selected from H, optionally substituted C.sub.1-12
alkyl, optionally substituted arenes, optionally substituted
C.sub.1-12 alkarenes, optionally substituted heteroarenes, or
optionally substituted C.sub.1-2 alkheteroarene; and X is a
pseudohalide.
[0074] By "alkyne" is meant a functional group having the structure
R.sup.1R.sup.2C.ident.CR.sup.2 wherein R.sup.1 is a bond or an
attachment to the graftable monomer, graftable polymer, or surface
and R.sup.2 is selected from H, optionally substituted C.sub.1-12
alkyl, optionally substituted arenes, or optionally substituted
heteroarenes. Preferred alkynes are those in which R.sup.2 is H,
optionally substituted C.sub.1-12 alkyl, or an optionally
substituted arene.
[0075] By "amino group" is meant a functional group having the
structure R.sup.1--NH.sub.2 wherein R.sup.1 is a bond or an
attachment to the graftable monomer, graftable polymer, or
surface.
[0076] By "amount sufficient" is meant the amount of biologically
active agent necessary to achieve a desired result. The amount
sufficient will vary depending upon a variety of parameters,
including the condition being treated (e.g., pain or microbial
growth, among others), the site being treated, the biologically
active agent selected, and the delivery vehicle employed (e.g.,
implanted device, cream, or pellet, among others). A sufficient
amount can be determined for any given set of conditions using
standard methods. For example, the release of biologically active
agent from a surface can be monitored as a function of the
parameters above. Based upon these results, a vehicle prepared
which releases the agent at a rate that produces the desired
effect.
[0077] By "anilido group" is meant a functional group having the
structure R.sup.1R.sup.2NH or R.sup.1-R.sup.2--NH.sub.2 wherein
R.sup.1 is a bond or an attachment to the graftable monomer,
graftable polymer, or surface and R.sup.2 is an optionally
substituted arene.
[0078] By "arene" is meant is an optionally substituted
C.sub.6-C.sub.14 cyclic hydrocarbon with [4n+2].pi. electrons in
conjugation and where n is 1, 2, or 3. Non-limiting examples of
arenes include benzene, naphthalene, anthracene, and
phenanthrene.
[0079] By "azide" is meant a functional group that includes at
least one --N.sub.3 functional group.
[0080] By "base polymer" is meant a polymer having a tensile
strength of from about 350 to about 10,000 psi, elongation at break
from about 300% to about 1500%, an unsupported thickness of from
about 5 to about 100 microns, and a supported thickness of from
about 1 to about 100 microns. Base polymers may be selected from:
polysilicones (also known as polysiloxanes), polyurethanes, latex
that is naturally occurring or synthetic, polysulfones,
polycarbonates, polysaccharides, polyesters, polyorthoesters,
polyalkylenes, polyethylene, polypropylene, polystyrene,
poly(acrylonitrile-butadienestyrene), polybutadiene, polyisoprene,
styrenebutadiene-styrene block copolymers, styrene-isoprenestyrene
block copolymers, poly-R-methylpentene, polyisobutylene,
polymethyl-methacrylate, polyvinylacetate-polyacrylonitrile,
polyvinylchloride, polyalkylene terephthalates,
polyethyleneterephthalate (also known as Dacron),
polyalkyleneoxides, cellulose and its esters and derivatives,
polyamides, polyester-polyethers, styrene-isoprenes,
styrenebutadienes, thermoplastic polyolefins, styrene-saturated
olefins, polyester-polyester, ethylene-vinyl acetate ethylene-ethyl
acrylate, ionomers, and thermoplastic polydienes, or mixtures or
blends thereof. Preferred base polymers are polysilicones,
polyurethanes, latex, polyethyleneterephthalate, and
polyvinylchloride, or mixtures or blends thereof.
[0081] By "biologically active agent" is meant a molecule that can
be coupled to a polyamide linker via a hydrolysable covalent bond.
The biologically active agent is selected for some specific and
intended physical, pharmacological, or biological action. Typically
the biologically active agent has a molecular weight ranging from
40 to 2,000 Da. Biologically active agents that can be used in the
methods and compositions of the invention include, without
limitation, anti-inflammatory, anti-oxidant, anti-coagulant,
anti-microbial (i.e. fluoroquinolones), cell receptor ligands, and
bio-adhesive molecules (e.g., oligosaccharides, oligonucleic acid
sequences for DNA and gene sequence bonding, and phospholipid head
groups to provide cell membrane mimics). Desirably, the
biologically active agent is a compound useful for the therapeutic
treatment of a plant or animal when delivered to a site of diseased
tissue. Alternatively, the biologically active agent can be
selected to impart non-therapeutic functionality to a surface. Such
agents include, for example, pesticides, bactericides, fungicides,
fragrances, and dyes.
[0082] By "carbene" is meant a functional group that is a divalent
carbon species having six valence electrons and the structure
R.sup.1R.sup.2C or R.sup.1-R.sup.2CR.sup.3 wherein R.sup.1 is a
bond or an attachment to the graftable monomer, graftable polymer,
or surface; R.sup.2 and R.sup.3 are, independently, selected from
H, optionally substituted C.sub.1-12 alkyl, optionally substituted
arenes, optionally substituted C.sub.1-12 alkarenes or optionally
substituted carbonyl; and C is a carbon with two electrons that are
not part of a covalent bond. The two electrons may be paired (e.g.
singlet carbene) or unpaired (e.g. triplet carbene).
[0083] By "catalyst" is meant a chemical or biological reagent that
is used in a substoichiometric quantity that accelerates the rate
of a reaction without being consumed. The use of a catalyst can
also result in improved chemical yields from a reaction. Types of
catalysts that are useful in the synthesis or the grafting of
graftable polymers include, but are not limited to enzymes, RNA,
DNA, Lewis acid catalysts, and Lewis basic catalysts that are known
in the art. Heterogeneous and homogeneous catalysis may both be
useful.
[0084] By "ceramics" is meant a material selected from metal oxides
or phosphates that include Ca.sub.5(PO.sub.4).sub.3(OH)
(hydroxyapatite), TiO.sub.2, Al.sub.2O.sub.3, ZrO.sub.2 (zirconia),
SiO.sub.2, or ZnO, or any composite thereof. The ceramic may
further include mineral acids such as hydrochloric acid, sulfuric
acid, nitric acid.
[0085] By "component of a coupling reaction" is meant one of the
components that engage in a coupling reaction that include either
the .sigma. bond or the .pi. bond that engages in the coupling
reaction. Components of coupling reactions include hydridosilanes,
alkenes, and alkynes.
[0086] By "component of a cycloaddition reaction" is meant one of
the components that engage in a cycloaddition reaction. In
cycloaddition reactions in which bond formation involves [4n+2]
.pi. electrons where n is 1, one component will provide 2 .pi.
electrons and another component will provide 4 .pi. electrons.
Representative components of cycloaddition reactions that provide
2.pi. electrons include alkenes and alkynes. Representative
components of cycloaddition reactions that provide 4.pi. electrons
include 1,3-dienes, .alpha., .beta.-unsaturated carbonyls, and
azides.
[0087] By "coupling reaction" is meant a reaction including two
components in which one component includes a nonpolar .sigma. bond
such as Si--H or C--H and the second component includes a .pi. bond
such as an alkene or an alkyne that results in either the net
addition of the .sigma. bond across the .pi. bond to form C--H,
Si--C, or C--C bonds or the formation of a single covalent bond
between the two components. A preferential coupling reaction is the
addition of Si--H across an alkene (also known as hydrosilylation).
Other coupling reactions include Stille coupling, Suzuki coupling,
Sonogashira coupling, Hiyama coupling, and the Heck reaction.
Catalysts may be used to promote the coupling reaction.
Preferential catalysts are those which include Pt(0), Pt(II), or
Pt(IV).
[0088] By "coupling segment" is meant a molecule or chemical bond
covalently linking segments together in the graftable polymer.
Typically, coupling segments can have molecular weights ranging
from 16 to 2000 Da and have multi-functionality, but preferably
di-functionality, to permit coupling of two segments. The coupling
segments can be synthesized from the groups of precursor monomers
selected from diols, diamines and/or a compounds containing both
amine and hydroxyl groups. Precursors that can be incorporated into
coupling segments include, without limitation, ethylene glycol,
butanediol, hexanediol, hexamethylenediol, 1,5 pentanediol,
2,2-dimethyl-1,3-propanediol, 1,4-cyclohexanediol,
1,4-cyclohexanedimethanol, tri(ethylene glycol), poly(ethylene
glycol), poly(ethylene oxide)diamine, lysine esters, siliconediols
and -diamines, polyetherdiols and -diamines, carbonatediols and
-diamines, dihydroxy vinyl derivatives, dihydroxy diphenylsulfone,
ethylenediamine, hexamethylenediamine, 1,2-diamino-2-methylpropane,
3,3-diamino-N-methyldipropylamine, 1,4 diaminobutane,
1,7-diaminoheptane, or 1,8-diaminooctane.
[0089] By "cycloaddition reaction" is meant a reaction including
two components in which [4n+2] .pi. electrons are involved in bond
formation when there is either no activation, activation by a
chemical catalyst, or activation using thermal energy and n is 1,
2, or 3. A cycloaddition reaction may also be a reaction including
two components in which [4n] .pi. electrons are involved, there is
photochemical activation, and n is 1, 2, or 3. Desirably, [4n+2]
.pi. electrons are involved in bond formation and n=1.
Representative cycloaddition reactions include the reaction of an
alkene with a 1,3-diene (Diels-Alder reaction), the reaction of an
alkene with an .alpha.,.beta.-unsaturated carbonyl (hetero
Diels-Alder reaction), and the reaction of an alkyne with an azide
(Huisgen cycloaddition).
[0090] By "electrophile" or "electrophilic group" is meant a
functional group that engages in the formation of a covalent bond
by accepting electrons or it may refer to a functional group that
is a precursor to an electrophile. Electrophiles may be selected
from nitrenes; nitrene precursors such as azides; carbenes; carbene
precursors; activated silicon centers; activated carbonyls; alkyl
halides; alkyl pseudohalides; epoxides; electron-deficient arenes;
activated phosphorus centers; and activated sulfur centers.
Preferential electrophiles are nitrenes, nitrene precursors, and
activated silicon centers.
[0091] By "epoxide" is meant an optionally substituted
three-membered heterocycle consisting of two optionally substituted
carbons and one oxygen.
[0092] By "fluoroquinolone" is meant a class of antibiotics which
exert their antibacterial effects by inhibiting bacterial DNA
gyrase and which include a fluorinated quinolone ring system.
Fluoroquinolone which can be used in the polymers and articles of
the invention include, without limitation, those described in
patent publications BE870576; DE3142854; EP047005; EP206283;
BE887574; EP221463; EP140116; EP131839; EP154780; EP078362;
EP310849; EP520240; and U.S. Pat. Nos. 4,448,962; 4,499,091;
4,704,459; 4,795,751; 4,668,784; and 5,532,239, each of which is
incorporated herein by reference. Exemplary fluoroquinolones which
can be used in the polymers and articles of the invention include,
without limitation, ciprofloxacin (commercially available as
Cipro.RTM.), enrofloxacin (commercially available as Baytril.RTM.),
enoxacin (commercially available as Penetrex.RTM., gatifloxacin
(commercially available as Tequin.RTM.), gemifloxacin (commercially
available as Factive.RTM.), levofloxacin (commercially available as
Levaquin.RTM.), lomefloxacin (commercially available as
Maxaquin.RTM.), moxifloxacin (commercially available as
Avelox.RTM.), norfloxacin (commercially available as Noroxin.RTM.),
ofloxacin (commercially available as Floxin.RTM.), sparfloxacin
(commercially available as Zagam.RTM.), trovafloxacin (commercially
available as Trovan.RTM.), difloxacin, cinofloxacin, pefloxacin,
tosufloxacin, temafloxacin, fleroxacin, amifloxacin, binfloxacin,
danofloxacin, marbofloxacin, ruflocaxin, and sarafloxacin.
[0093] By "graftable polymer" is meant a pharmaceutically active
polymer that includes a grafting moiety.
[0094] By "grafting" is meant the covalent attachment of a
graftable polymer to a surface (e.g., the surface of a base
polymer, a ceramic surface, or a metal surface) through the
formation of covalent bonds between the graftable polymer and the
surface. Covalent attachment may occur, for example, through the
formation of C--H, C--C, C--N, C--O, C--S, C--Si, Si--H, Si--N,
Si--O, Si--S, Si--Si, N--H bonds, C-metal bonds, N-metal bonds,
Si-metal bonds, O-metal bonds, or any combination thereof. For
example, grafting can occur through the formation of Si--O, Si--C,
or C--N bonds. Covalent attachment can result from combining the
two entities, but may also employ an additional activation step in
order to promote the reaction. Methods of activation may be
selected from chemical treatment of the graftable polymer, chemical
treatment of the surface, photolytic activation, thermolytic
activation, use of a catalyst, use of stoichiometric or
superstoichiometric quantities of a promoter, by other means known
in the art, or by any combination of the methods listed.
Preferential methods of activation are the chemical treatment of
the surface, photolytic activation, and the use of a catalyst.
[0095] By "grafting moiety" or "graftable moiety" is meant a
functional group capable of forming covalent bonds to a surface by
acting as a nucleophile, electrophile, a component in a
cycloaddition reaction, or a component in a coupling reaction as
described herein to allow grafting.
[0096] By "grafted moiety" is meant a segment of a pharmaceutically
active polymer that includes a functional group that is covalently
tethered to a surface by grafting.
[0097] By "halide," "halogen," "hal," or "halo" is meant --F, --Cl,
--Br, or --I.
[0098] By "heteroarene" is meant an optionally substituted cyclic
moiety formed with 5-18 atoms selected from C, S, N, and O and
having [4n+2] .pi. electrons in conjugation where n=1-3 wherein at
least one atom forming the ring is S, N, or O, Non-limiting
examples of heteroarenes include furan, benzofuran, isobenzofuran,
thiophene, benzothiophene, pyrrole, indoles, pyrazoles, imidazole,
benzimidazole, triazoles, benzotriazoles, thiazoles,
benzothiazoles, oxazoles, benzoxazoles, oxadiazoles, thiadiazoles,
pyridines, pyrimidines, pyrazines, triazines, purines, phthalzine,
quinolines, isoquinolines, and quinazolines.
[0099] By "hydridosilane" is meant a grafting moiety that includes
a tetrasubstituted silicon center wherein at least one of the
substituents is a hydrogen.
[0100] By "hydroxy group" or "hydroxyl group" is meant a functional
group having the structure R.sup.1--OH wherein R.sup.1 is a bond or
an attachment to the graftable monomer, graftable polymer, or
surface.
[0101] By "metal" or "metallic surface" is meant a material
comprising at least one of the metallic elements of Groups 2-14 in
the Periodic Table, or any alloy thereof, or any surface oxide
thereof. Exemplary metals are: aluminum, cadmium, chromium, cobalt,
copper, gold, iridium, iron, magnesium, molybdenum, nickel,
palladium, platinum, silver, titanium, and zinc. Exemplary alloys
are: cobalt/chromium alloys; silver alloys; stainless steel, such
as stainless steel 316; and titanium alloys, such as
nickel/titanium alloys (e.g. Nitinol). Other exemplary metallics
include pyrolytic carbon.
[0102] By "nitrene" is meant a functional group that is a
monovalent nitrogen species having six valence electrons and the
structure R.sup.1N or R.sup.1-R.sup.2--N wherein R.sup.1 is an
attachment to the graftable monomer, graftable polymer, or surface;
R.sup.2 is selected from optionally substituted C.sub.1-12 alkyl,
optionally substituted arenes, optionally substituted C.sub.1-12
alkarenes, or optionally substituted carbonyl; and N is a nitrogen
with four electrons, at least two of which are paired. The two
remaining electrons may be paired (i.e. singlet nitrene) or
unpaired (i.e. triplet nitrene).
[0103] By "nonpolar a bond" is meant a covalent bond between two
elements having electronegativity values, as measured according to
the Pauling scale, that differ by less than or equal to 1.0 units.
Non-limiting examples of nonpolar a bonds include C--H, Si--H,
Si--C, C--Cl, C--Br, C--I, C--B, and C--Sn bonds.
[0104] By "nucleophile" or "nucleophilic functional group" is meant
an optionally substituted functional group that engages in the
formation of a covalent bond by donating electrons from electron
pairs or .pi. bonds. In describing grafting moieties that include
nucleophiles, it is understood that the functional group will have
at least one bond to the graftable monomer, graftable polymer, or a
surface. Nucleophiles may be selected from alkenes, alkynes,
arenes, heteroarenes, hydroxy groups, phenoxy groups, amino groups,
alkylamino groups, anilido groups, thio groups, and thiophenoxy
groups. Preferential nucleophiles are hydroxy groups and
alkenes.
[0105] By "oligomeric segment" or "Oligo" is meant a unit included
of a relatively short length of a repeating unit or units,
generally less than about 50 monomeric units and molecular weights
less than 10,000 but preferably <5000. Preferably, the
oligomeric segment is selected from the group consisting of
polyurethanes, polyureas, polyamides, polyalkylene oxides,
polycarbonates, polyesters, polylactones, polysilicones,
polyethersulfones, polyolefins, polyvinyls, polypeptides,
polysaccharides; and ether and amine linked segments thereof.
Preferred oligomeric segments are polyurethanes.
[0106] By "pharmaceutically active polymer" is meant a polymer that
includes a biologically active agent and a grafting moiety as
described above.
[0107] By "phenoxy group" or "phenoxyl group" is meant a functional
group having the structure R.sup.1-R.sup.2--OH wherein R.sup.1 is a
bond or an attachment to the graftable monomer, graftable polymer,
or surface and R.sup.2 is an optionally substituted arene.
[0108] By "photolytic activation" or "photolysis" is meant the
promotion or initiation of a chemical reaction by irradiation of
the reaction with light. The wavelengths of light suitable for
photolytic activation range between 200-500 nm and include
wavelengths that range from 200-260 nm and 300-460 nm. Other useful
ranges include 200-230 nm, 200-250 nm, 200-275 nm, 200-300 nm,
200-330 nm, 200-350 nm, 200-375 nm, 200-400 nm, 200-430 nm, 200-450
nm, 200-475 nm, 300-330 nm, 300-350 nm, 300-375 nm, 300-400 nm,
300-430 nm, 300-450 nm, 300-475 nm, and 300-500 nm.
[0109] By "chemical treatment" is meant the combination or
admixture of the graftable polymer or the surface with a chemical
or a solution of a chemical. Chemical that may be used in such
processes are: inorganic acids such as HCl, H.sub.2SO.sub.4,
HNO.sub.3, H.sub.3PO.sub.4, or any mixture thereof; organic acids
such as acetic acid; and organosilane reagents such as
trimethylsilyl chloride, acteoxysilanes, alkyoxysilanes. The
organosilane reagents are also known as "tie-coats."
[0110] By "prodrug" is meant a precursor to a biologically active
agent that is converted in vivo, e.g., by enzymatic and/or
hydrolytic mechanisms, into a biologically active agent. Prodrugs
include, without limitation, esterified biologically active
agents.
[0111] By "promoter" is meant a reagent used in a stoichiometric or
superstoichiometetric quantity that can accelerate the rate of a
reaction or improve chemical yields of a reaction. Examples of
promoters include N,N-dimethylaminopyridine (DMAP) for nucleophilic
additions, carboxylic acid activators such as
dicyclohexylcarbodiimide (DCC) and peptide coupling reagents known
in the art.
[0112] Bond formation in this manner requires that the graftable
polymer and/or the surface include a grafting moiety, such as a
nucleophile, electrophile, a component of a cycloaddition reaction,
a component of a coupling reaction, or a component of a radical
recombination reaction. For example, where the graftable polymer
includes a nucleophile, the surface is designed to include an
electrophile.
[0113] By "pseudohalide" is meant a polyatomic functional group
having the structure selected from: --OSO.sub.2C.sub.nF.sub.(2n+1)
where n=1-9; --OSO.sub.2R.sup.1 where R.sup.1 is optionally
substituted C.sub.1-6 alkyl or optionally substituted arene; or
--OSO.sub.3R.sup.1, where R.sup.1 is optionally substituted
C.sub.1-6 alkyl or optionally substituted arene.
[0114] By "thermal activation," "thermolytic activation," or
"thermolysis" is meant the promotion or initiation of a chemical
reaction by the application of heat to the system. Thermal
activation occurs at temperatures above 25-30.degree. C. (ambient
temperature) and useful reaction temperatures range from
40-800.degree. C. Other useful temperature ranges for thermolysis
include 40-100.degree. C., 40-200.degree. C., 40-300.degree. C.,
40-400.degree. C., 40-500.degree. C., 40-600.degree. C.,
40-700.degree. C., 100-200.degree. C., 100-300.degree. C.,
100-400.degree. C., 100-500.degree. C., 100-600.degree. C.,
100-700.degree. C., 100-800.degree. C., 200-300.degree. C.,
200-400.degree. C., 200-500.degree. C., 200-600.degree. C.,
200-700.degree. C., 200-800.degree. C., 300-400.degree. C.,
300-500.degree. C., 300-600.degree. C., 300-700.degree. C., and
300-800.degree. C. The reaction may be carried out under
atmospheric pressure but the use of reduced pressure (i.e. vacuum
conditions) may also be useful in thermolytic activation. When
reduced pressure is used during thermolysis, useful pressures range
from 1.times.10.sup.-8-1.times.10.sup.2 torr. Other useful pressure
ranges include: 1.times.10.sup.-8-1 torr;
1.times.10.sup.-8-1.times.10.sup.-2 torr;
1.times.10.sup.-1.times.10.sup.-4 torr;
1.times.10.sup.-8-1.times.10.sup.-6 torr;
1.times.10.sup.-6-1.times.10.sup.2 torr; 1.times.10.sup.-6-1 torr;
1.times.10.sup.-6-1.times.10.sup.-2 torr;
1.times.10.sup.-6-1.times.10.sup.-4 torr;
1.times.10.sup.-4-1.times.10.sup.2 torr; 1.times.10.sup.-4-1 torr;
1.times.10.sup.-4-1.times.10.sup.-2 torr;
1.times.10.sup.-2-1.times.10.sup.2 torr; and 1.times.10.sup.-2 1
torr.
[0115] By "thio group" or "thiol group" is meant a functional group
having the structure R.sup.1SH wherein R'' is a bond or an
attachment to the graftable monomer, graftable polymer, or
surface.
[0116] By "thiophenoxy group" or "thiophenoxyl group" is meant a
functional group having the structure R.sup.1-R.sup.2--SH wherein
R.sup.1 is a bond or an attachment to the graftable monomer,
graftable polymer, or surface and R.sup.2 is an optionally
substituted arene.
[0117] Where a group is described as "optionally substituted," the
optional substituents may be selected, independently, from H;
C.sub.1-10 alkyl; C.sub.1-10 perfluorinated alkyl; halo; --N.sub.3,
--NO.sub.2; --CN; --COR.sup.4 wherein R.sup.4 is selected,
independently, from --H, --OH, --C.sub.1-10 alkyl, --C.sub.1-10
alkoxy, -halo, --N.sub.3, or --NR.sup.5R.sup.6; --NR.sup.5R.sup.6,
wherein R.sup.5 and R.sup.6 are selected, independently, from --H,
-aryl, -alkaryl, -heteroaryl, -alkheteroaryl, --C.sub.1-10 alkyl,
--C.sub.1-10 alkoxy, or --COR.sup.4; -aryl; -alkaryl; -heteroaryl;
-alkheteroaryl; --SR.sup.7, wherein R.sup.7 is selected from --H,
--C.sub.1-10 alkyl, -aryl, -alkaryl, -heteroaryl, -alkheteroaryl,
or --C.sub.10 alkyl; --OR.sup.8 wherein R.sup.8 is selected from
--H, -aryl, -alkaryl, -heteroaryl, -alkheteroaryl, --C.sub.1-10
alkyl, --C.sub.1-10 perfluorinated alkyl, or --COR.sup.4;
--SOR.sup.9 wherein R.sup.9 is selected from --H, -aryl, -alkaryl,
-heteroaryl, -alkheteroaryl, --OH, --C.sub.1-10 alkyl, --C.sub.1-10
alkoxy, or --C.sub.1-10 perfluorinated alkyl; and
--SO.sub.2R.sup.10, wherein R.sup.10 is selected from --H, -aryl,
-alkaryl, -heteroaryl, -alkheteroaryl, --OH, --C.sub.1-10 alkyl,
--C.sub.1-10 alkoxy, or --C.sub.1-10 perfluorinated alkyl. A
substituted group may have, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9,
or 10 substituents as defined herein. A substituent group may
itself be further substituted.
[0118] Other features and advantages of the invention will be
apparent from the following Detailed Description, the drawings, and
the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0119] FIG. 1 shows the minimum inhibitory concentration (MIC)
measured against an Escherichia coli (E. coli) clinical strain for
pharmaceutical released from Polymer 17 (depicted in Scheme 5 and
as prepared in Example 5).
[0120] FIG. 2 shows the release of Ciprofloxacin as measured by
HPLC by Polymer 17.
[0121] FIG. 3 shows the minimum inhibitory concentration (MIC)
measured against an E. coli clinical strain for pharmaceutical
released from Polymer 19 (depicted in Scheme 5 and as prepared in
Example 5).
[0122] FIG. 4 shows the release of Ciprofloxacin as measured by
HPLC by Polymer 19.
[0123] FIG. 5 shows the minimum inhibitory concentration (MIC)
measured against an E. coli clinical strain for pharmaceutical
released from Polymer 18 (depicted in Scheme 5 and as prepared in
Example 5) grafted onto a silicone surface according to Example
10.
[0124] FIG. 6 shows the minimum inhibitory concentration (MIC)
measured against an E. coli clinical strain for Polymer 18 grafted
to a silicone surface using triacetoxymethylsilane as a tie-coat
according to the procedure of Example 11.
[0125] FIG. 7 shows the minimum inhibitory concentration (MIC)
measured against an E. coli clinical strain for pharmaceutical
released from Polymer 21 (depicted in Scheme 6 and as prepared in
Example 7) grafted onto a polyurethane surface according to the
procedure of Example 13.
[0126] FIG. 8 shows the release of Ciprofloxacin as measured by
HPLC by Polymer 21 (depicted in Scheme 6 and as prepared in Example
7) when grafted to polyvinylchloride (PVC) surfaces according to
the procedure of Example 13.
[0127] FIG. 9 shows the release of Ciprofloxacin as measured by
HPLC by Polymer 21 (depicted in Scheme 6 and as prepared in Example
7) when grafted to silicone and polyurethane surfaces according to
the procedure of Example 13.
[0128] FIG. 10 shows the effect on the plate count of S. aureus
using silicone tubing coated with a mixture of
ciprofloxacin-containing polymers and tie-coats, silver-coated
tubing, and uncoated tubing as described in Example 19.
DETAILED DESCRIPTION
[0129] The invention features graftable polymers including
biologically active agents and the use of such polymers in the
manufacture of shaped articles, such as implantable medical devices
and catheters. The graftable polymers are covalently grafted to a
surface via one or more grafting moieties incorporated into the
pharmaceutically-active graftable polymer. The surfaces that can be
modified using the graftable polymers of the invention include, for
example, polysilicone base polymers, latex base polymers,
polyvinylchloride base polymers, ceramic surfaces, and metallic
surfaces. These pharmaceutically active polymers can allow for the
manufacture of shaped articles and implantable medical devices with
increased longevity that will maintain pharmaceutical efficacy for
the desired time period as well as retain the desirable properties
of the base polymer.
Grafting Moieties
[0130] The graftable, pharmaceutically-active polymers of the
invention feature a grafting moiety that can form covalent bonds
with a surface. The graftable moiety may be found along the main
chain of the polymer or may be pendant from the main chain.
Representative, non-limiting grafting moieties include:
nucleophiles, electrophiles, components of a cycloaddition
reaction, or components of a coupling reaction. The graftable
moiety of the polymer can then react with complementary
functionality on the surface. For example, where the graftable
polymer includes a nucleophile, the surface is designed to include
an electrophile.
[0131] Nucleophile/Electrophile Reactions
[0132] Nucleophiles and electrophiles can engage in bond forming
reactions selected from, without limitation, insertion by an
electrophile into a C--H bond, insertion by an electrophile into an
O--H bond, insertion by an electrophile into an N--H bond, addition
of the electrophile across an alkene, addition of the electrophile
across an alkyne, addition to electrophilic carbonyl centers,
substitution at electrophilic carbonyl centers, addition to
ketenes, nucleophilic addition to isocyanates, nucleophilic
addition to isothiocyanates, nucleophilic substitution at activated
silicon centers, nucleophilic displacement of an alkyl halide,
nucleophilic displacement at an alkyl pseudohalide, nucleophilic
addition/elimination at an activated carbonyl, 1,4-conjugate
addition of a nucleophile to an .alpha., .beta.-unsaturated
carbonyl, nucleophilic ring opening of an epoxide, nucleophilic
aromatic substitution of an electron deficient arene, a
nucleophilic addition to activated phosphorus centers, nucleophilic
substitution at activated phosphorous centers, nucleophilic
addition to activated sulfur centers, and nucleophilic substitution
at activated sulfur centers.
[0133] Nucleophiles
[0134] The graftable moiety may be selected from optionally
substituted alkenes, optionally substituted alkynes, optionally
substituted arenes, optionally substituted heteroarenes, hydroxy
groups, amino groups, alkylamino groups, anilido groups, and thio
groups.
[0135] Electrophiles
[0136] The graftable moiety may be selected from nitrenes, nitrene
precursors such as azides, carbenes, carbene precursors, activated
silicon centers, activated carbonyls, anhydrides, isocyanates,
thioisocyanates, succinimidyl esters, sulfosuccinimidyl esters,
maleimides, alkyl halides, alkyl pseudohalides, epoxides,
electron-deficient arenes, activated phosphorus centers, and
activated sulfur centers. Examples of polysiloxanes that include
activated silicon centers as an electrophilic grafting moiety and
that are suitable for use in the graftable polymers of the
invention are compounds (1)-(4).
##STR00014##
[0137] Alternatively, the pharmaceutically active polymer may
include a graftable moiety that requires photolytic or thermolytic
activation for grafting to a polymer surface. Graftable moieties
that include azide functionality are one example. The azide
functional groups are UV labile and, upon photolysis, can lead to
the formation of nitrene electrophiles. Alternatively, the heating
of these azide compounds can also result in nitrene formation. Two
photolytically active segment suitable for use in the graftable
pharmaceutically active polymers of the invention include compounds
(5) and (6).
##STR00015##
[0138] Components of Coupling Reactions
[0139] Coupling reactions can be used to form covalent bonds
between the graftable polymers of the invention and surfaces.
Coupling reactions can include but are not limited to:
hydrosilylation, Stille coupling, Suzuki coupling, Sonogashira
coupling, Hiyama coupling, and the Heck reaction. Selected,
non-limiting examples of graftable moieties that include components
of coupling reactions are hydridosilanes, alkenes, and alkynes. An
exemplary graftable moiety that includes hydridosilane functional
groups and that is suitable for use in the graftable
pharmaceutically active polymers of the invention is compound
(7).
##STR00016##
[0140] Components of Cycloaddition Reactions.
[0141] Cycloadditon reactions can be used to form covalent bonds
between the graftable polymers of the invention and surfaces.
Representative cycloaddition reactions include the reaction of an
alkene with a 1,3-diene (Diels-Alder reaction), the reaction of an
alkene with an .alpha.,.beta.-unsaturated carbonyl (hetero
Diels-Alder reaction), and the reaction of an alkyne with an azide
(Huisgen cycloaddition). Selected, non-limiting examples of
graftable moieties that include components of cycloaddition
reactions are: alkenes, alkynes, 1,3-dienes,
.alpha.,.beta.-unsaturated carbonyls, and azides.
Surfaces
[0142] The graftable, pharmaceutically-active polymers of the
invention can be grafted to a surface, such as a ceramic surface,
metallic surface, or the surface of a base polymer. Exemplary
reactions that can lead to the formation of covalent bonds between
the graftable polymers of the invention and surfaces include
electrophile/nucleophile reactions, coupling reactions, photolysis
of UV-labile graftable moieties, and thermolysis of nitrene
precursors.
[0143] Base Polymers
[0144] Examples of base polymers to which the graftable,
pharmaceutically-active polymer may be grafted include, but are not
limited to, polysilicones (also known as polysiloxanes),
polyurethanes, latex that is naturally occurring or synthetic,
polysulfones, polycarbonates, polysaccharides, polyesters,
polyorthoesters, polyalkylenes, polyethylene, polypropylene,
polystyrene, poly(acrylonitrile-butadienestyrene), polybutadiene,
polyisoprene, styrenebutadiene-styrene block copolymers,
styrene-isoprenestyrene block copolymers, poly-R-methylpentene,
polyisobutylene, polymethyl-methacrylate,
polyvinylacetate-polyacrylonitrile, polyvinyl chloride,
polyalkylene terephthalates, polyethyleneterephthalate (also known
as Dacron), polyalkyleneoxides, cellulose and its esters and
derivatives, polyamides, polyester-polyethers, styrene-isoprenes,
styrenebutadienes, thermoplastic polyolefins, styrene-saturated
olefins, polyester-polyester, ethylene-vinyl acetate ethylene-ethyl
acrylate, ionomers, and thermoplastic polydienes, or mixtures or
blends thereof.
[0145] Graftable polymers may form covalent bonds to polysilicone
surfaces through reactions that include nucleophile/electrophile
reactions. Examples of nucleophile/electrophile reactions for the
covalent linkage of a graftable polymer to a polysilicone surface
include but are not limited to: substitution at electrophilic
carbonyl centers, nucleophilic addition to ketenes, nucleophilic
addition to isocyanates, nucleophilic addition to isothiocyanates,
nucleophilic addition at activated silicon centers, nucleophilic
substitution at activated silicon centers, nucleophilic
displacement of an alkyl halide, nucleophilic displacement at an
alkyl pseudohalide, addition/elimination at an activated carbonyl,
1,4-conjugate addition of a nucleophile to an
.alpha.,.beta.-unsaturated carbonyl, nucleophilic ring opening of
an epoxide, nucleophilic aromatic substitution of an electron
deficient arene, nucleophilic addition at activated phosphorous
centers, nucleophilic addition at activated phosphorous centers,
nucleophilic substitution at activated phosphorous centers,
nucleophilic addition at activated sulfur centers, and nucleophilic
substitution at activated sulfur centers. For example, the grafting
moiety may be an electrophile as exemplified by compounds (1)-(4)
that include activated silicon centers.
[0146] The polysilicone surfaces may further include tie coats such
as acetoxysilane additives. Preferred acetoxysilane additives for
the treatment of polysilicone surfaces include tert-butyloxy
triacetoxysilane, ethyl triacetoxysilane (ETAS), and methyl
triacetoxysilane (MTAS).
[0147] Graftable polymers can form covalent bonds to the surfaces
of base polymers such as polyurethanes through reactions that
include nucleophile/electrophile reactions. Examples of suitable
nucleophile/electrophile reactions include but are not limited to:
insertion by an electrophile into a C--H bond, insertion by an
electrophile into an N--H bond, substitution at electrophilic
carbonyl centers, nucleophilic addition to isocyanates, or
addition/elimination at an activated carbonyl. UV labile grafting
moieties such as compounds (5) and (6) can be used to form covalent
bonds between the graftable polymer and the polyurethane
surface.
[0148] Alternatively, graftable polymers may form covalent bonds to
polyvinylchloride surfaces through reactions that include
nucleophile/electrophile reactions. Examples of suitable
nucleophile/electrophile reactions include but are not limited to:
insertion by an electrophile into a C--H bond, insertion by an
electrophile into an N--H bond, substitution at electrophilic
carbonyl centers, nucleophilic addition to isocyanates, or
addition/elimination at an activated carbonyl. Again, UV labile
grafting moieties such as compounds (5) and (6) can be used to form
covalent bonds between the graftable polymer and the
polyvinylchloride surface.
[0149] Graftable polymers may form covalent bonds to latex surfaces
through reactions that include but are not limited to coupling
reactions. Examples of coupling reactions that can be useful for
grafting to a latex surface are: hydrosilylation, Stille coupling,
Suzuki coupling, Sonogashira coupling, Hiyama coupling, and the
Heck reaction. Grafting moieties that include hydridosilanes (e.g.
compound (7)) can be used to form covalent bonds between a
graftable polymer and a latex surface.
[0150] The latex surfaces may further include alkoxysilane
additives. Non-limiting examples of alkoxysilane additives include:
(OR).sub.3SIH wherein R can be methyl, ethyl, or acetyl;
(OR).sub.2(CH.sub.3)SiH wherein R can be methyl, ethyl, or acetyl;
or (OR)(CH.sub.3).sub.2SiH wherein R is methyl, ethyl, or
acetyl.
[0151] The grafting of a graftable, pharmaceutically active polymer
to a base polymer can benefit from the use of promoters and
catalysts. Methods that may be used in grafting can be selected
from: chemical treatment of the surface, photolytic activation,
thermolytic activation, use of a catalyst, by other means known in
the art, or by any combination of the methods listed. Catalysts may
be employed for the grafting of a pharmaceutically active polymer
to a base polymer. For pharmaceutically active polymers that
include activated polysiloxanes as the grafting moiety, the use of
catalysts such as dibutyltin dilaurate and dibutyltin octanoate may
be employed. For pharmaceutically active polymers that include
hydridosilanes as the grafting moiety, the use of Pt(0), Pt(II), or
Pt(IV) catalysts may be employed. In the chemical treatment of a
base polymer, the polymer may be treated with a tie coat (e.g.,
reactive silane reagents such as alkoxysilanes, acetoxysilanes, or
trimethylsilylchloride), mineral acids such as HCl,
H.sub.2SO.sub.4, or HNO.sub.3 or the polymer may be treated with
bases such as NaOH or KOH.
[0152] Ceramics
[0153] The graftable, pharmaceutically active polymers of the
invention may be grafted to a ceramic surface. Examples of ceramics
that may be used in the invention are Ca.sub.5(PO.sub.4).sub.3(OH)
(hydroxyapatite), TiO.sub.2, Al.sub.2O.sub.3, ZrO.sub.2 (zirconia),
SiO.sub.2, or ZnO, or any composite thereof.
[0154] In one example, graftable polymers may form covalent bonds
to ceramic surfaces through reactions that include
nucleophile/electrophile reactions. Such reactions can include, but
are not limited to: substitution at electrophilic carbonyl centers,
addition to ketenes, nucleophilic addition to isocyanates,
nucleophilic addition to isothiocyanates, nucleophilic substitution
at activated silicon centers, nucleophilic displacement of an alkyl
halide, nucleophilic displacement at an alkyl pseudohalide,
addition/elimination at an activated carbonyl, 1,4-conjugate
addition of a nucleophile to an .alpha.,.beta.-unsaturated
carbonyl, nucleophilic ring opening of an epoxide, nucleophilic
aromatic substitution of an electron deficient arene, nucleophilic
substitution at activated phosphorous centers, and nucleophilic
substitution at activated sulfur centers. In preferred embodiments,
the grafting moiety of the polymer can be an electrophilic,
activated silicon center (e.g. compounds (1)-(4)).
[0155] The grafting of a graftable, pharmaceutically active polymer
to a ceramic surface may benefit from the chemical treatment of the
ceramic. In the chemical treatment of the ceramic, the ceramic may
be treated with: a tie coat (e.g., reactive silane reagents such as
alkoxysilanes, acetoxysilanes, or trimethylsilylchloride); mineral
acids such as HCl, H.sub.2SO.sub.4, or HNO.sub.3; or with bases
such as NaOH or KOH. For example, mineral acids or alkoxide bases
can be used in the grafting to ceramic surfaces.
[0156] Metals
[0157] The graftable, pharmaceutically active polymers of the
invention may be grafted to the surface of a metal or an alloy
thereof. Exemplary metals useful in the invention are: aluminum,
cadmium, chromium, cobalt, copper, gold, iridium, iron, magnesium,
molybdenum, nickel, palladium, platinum, silver, titanium, and
zinc. Exemplary alloys are: cobalt/chromium alloys; silver alloys;
stainless steel, such as stainless steel 316; and titanium alloys,
such as nickel/titanium alloys (e.g. Nitinol). Other exemplary
metallies include pyrolytic carbon. In some embodiments, graftable
polymers may form covalent bonds to metal surfaces through
reactions that include nucleophile/electrophile reactions. In one
example, UV labile grafting moieties such as compounds (5) and (6)
can be used to form covalent bonds between the graftable polymer
and the metal surface.
Tie Coats
[0158] Exemplary chemical additives useful in the invention include
tie coats. Tie coats can be small molecules, polymers, or any
mixture thereof, and are additives that are used to improve
adhesion of a graftable polymer, mixture of graftable polymers, or
any composition thereof, to a surface. Tie coats may be applied to
a surface prior to coating with a graftable polymer or may be
applied to a surface as part of an mixture that includes a
graftable polymer. For example, tie coats can be applied to a
surface (e.g., the surface of a medical device) as a thin layer
(e.g., a layer ranging between 5-80 .mu.M or 5-20 .mu.M in
thickness) prior to application of the graftable polymer.
Alternatively, the tie coat, or mixture thereof, can be combined
with the graftable polymer, and the resulting mixture can then be
applied to a surface (e.g., the surface of a medical device).
Preferably, the tie coat is applied to a surface as a mixture with
the graftable polymer.
[0159] The ratio of a tie-coat to the graftable polymer can also be
varied (e.g., the weight:weight ("w/w") ratio of the graftable
polymer:tie coat reagent can range from, for example, 1:5 to 50:1).
For example, the range of the polymer:tie coat reagent (w/w) can be
2:1, 1:1, or 1:2. Tie coats used in the invention can be applied as
a solution in a solvent (e.g., THF). These solutions may also
include a graftable polymer, or mixtures thereof.
[0160] Without being bound by theory, the larger the ratio of drug
polymer to tie coat on the surface, the greater the concentration
of drug is available to be released on the surface. Accordingly,
the ratio of graftable polymer:tie coat can be adjusted in order to
produce the desired drug elution rate (e.g., a 2:1 ratio of
polymer:tie coat can lead to faster elution of the drug compared to
a 1:2 ratio; see, for example, FIG. 10). The rate of release of a
drug can also be affected by the method of application of the tie
coat (i.e., as a separate layer or as part of an admixture that
includes the graftable polymer).
[0161] The process of coating an article by applying a tie coat and
graftable polymer can be repeated as described herein in order to
achieve the desired coating thickness. The tie coat and graftable
polymer applied in each coating cycle can be the same or different
tie coat and graftable polymer that were previously applied.
Similarly, the ratios of the tie coat and graftable polymer (e.g.,
the w/w ratio of a mixture of tie-coat and graftable polymer) can
be the same or different in each coating cycle.
[0162] Exemplary, non-limiting tie coats include Dow Corning.RTM.
Q7-2360 and MDX4-42 tie coats, alkoxysilanes, acetoxysilanes such
as (AcO).sub.3Si(O.sup.tBu) ("TEAS"), (AcO).sub.3Si(OEt) ("ETAS"),
(AcO).sub.3Si(OMe) ("MTAS"), and functionalized small molecule and
polymeric silicon reagents such as those shown in Scheme 1.
##STR00017##
In addition to the combinations of tie coats and surfaces described
herein, Table 1 provides representative surfaces and exemplary,
non-limiting tie-coats that can be used in combination with the
surface and a graftable polymer as described herein.
TABLE-US-00001 TABLE 1 Surface Exemplary Tie Coats Stainless
Mixture of epoxy resin and vinylpyrrolidone-vinyl acetate steel
copolymers; styrene acrylic aqueous dispersion; Mixture of ethylene
acrylic acid copolymer and melamine resin; Mixture of ethylene
acrylic acid copolymer, melamine resin, hydroxyl functionalized
acrylic polymer, and isocyanate polymer; Mixture of carboxyl
functionalized acrylic polymer and epoxy resin; acrylic dispersion
polymer; Mixture of polysilicone, alkoxysilane, and acetoxysilanes.
Poly- Mixture of ethylene acrylic acid copolymers, melamine resin,
ethylene hydroxyl functionalized acrylic polymers, and isocyanate
polymers; Mixture of polysilicone, alkoxysilane, and
acetoxysilanes. Silicone Mixture of ethylene acrylic acid
copolymers, melamine resin, hydroxyl functionalized acrylic
polymers, and isocyanate polymers; Mixture of polysilicone,
alkoxysilane, and acetoxysilanes. Natural Mixture of ethylene
acrylic acid copolymers, melamine resin, rubber hydroxyl
functionalized acrylic polymers, and isocyanate polymers; Mixture
of polysilicone, alkoxysilane, and acetoxysilanes. Poly- Mixture of
ethylene acrylic acid copolymers, melamine resin, urethane hydroxyl
functionalized acrylic polymers, and isocyanate polymers; Mixture
of polysilicone, alkoxysilane, and acetoxysilanes. Polyester
Mixture of ethylene acrylic acid copolymers, melamine resin,
hydroxyl functionalized acrylic polymers, and isocyanate polymers;
Mixture of polysilicone, alkoxysilane, and acetoxysilanes.
Hydrolysable Coupling Segments and Polymamide Linkers
[0163] Polyamide linkers incorporated in the graftable,
pharmaceutically active polymers of the invention (e.g., C2 in
Formulas (III), (IV), (VII), and (VIII)) include natural amino
acids coupled through amide linkages in linear or branched
sequences. The polyamide linkers are designed to be susceptible to
hydrolysis by particular endopeptidase enzymes, such as
Staphylococcus aureus serine glutamyl endopeptidase, V8 protease,
metalloproteinases including aureolysin and MMP-9, and
exopeptidases such as carboxypeptidase A, carboxypeptidase B,
aminopeptidase N/CD, and aminopeptidase P, that are upregulated
during a physiological response or pathological process.
[0164] Hydrolysis of the polyamide linker occurs at specific
protease cleavage recognition sites. In particular, MMP-9 is known
to recognize and cleave several consensus sequences; including
Pro-X-X-Hy-(Ser/Thr), Gly-Leu-(Lys/Arg), Arg-Arg-X-(Ile/Lys), and
Arg-X-(Ile/Lys), where X is any residue and Hy is a hydrophobic
residue. MMP-9 has a unique preference for Arg at both P.sub.2 and
P.sub.1 and a preference for Ser/Thr at P.sub.2. V8 protease favors
glutamic acid and Pro or Leu at the P.sub.1 and P.sub.2 position,
respectively, while the S3 subsite of V8 protease prefers leucine.
Aureolysin has a low substrate specificity and cleaves bonds on the
N-terminal side of bulky, aliphatic, or hydrophobic residues.
Furthermore, human exopeptidases, carboxypeptidase B and
aminopeptidases N/CD, target basic residues (Arg/Lys) and Ala,
respectively.
[0165] To prepare a polymer susceptible to degradation by Cathepsin
K, the polyamide linker can include one of the following peptide
sequences specifically recognized by this enzyme: KLRFSKQEDD;
KXPGSKQEDD; and KPXGSKQEDD (see, for example, Alves et al.,
Biochem. J. 373:981 (2003)).
[0166] To prepare a polymer susceptible to degradation in the
presence of Candida albicans, the polyamide linker can include a
peptide sequence recognized by a peptidase enzyme expressed by this
organism (e.g., aspartyl proteinases expressed by C. albicans
recognize the peptide sequence SLASPPTSLVF)(see, for example,
Putnam et al., J. Biol. Chem. 254:2865 (1979)).
[0167] Polyamide linkers may incorporate non-natural or D-amino
acids and remain susceptible to hydrolysis by secreted prokaryotic
proteases. The V8 protease has a large hydrophobic pocket at its
P1' position and can digest a p-nitroanilide substrate. Secreted
Prokaryotic proteases may also recognize D-amino acids and
preferentially hydrolyze the polyamide linker in the presence of
Eukaryotic proteases
[0168] Polyamide linkers remain stable to exopeptidase activity
until hydrolysis by endopeptidases creates polyamide fragments with
free carboxy- or amino-termini. The need for aminopeptidases may be
minimized by locating endopeptidase cleavage sites at the
C-terminus of polyamide linkers attached to the biologically active
agent.
[0169] Because protease recognition sequences are generally only a
few amino acids in length, a relatively short polyamide linker can
contain several cleavage recognition sites. Polyamide linkers used
in the invention can range from 2 to 60 amino acids in length.
[0170] Additional examples of hydrolysable coupling segments and
polymamide linkers are disclosed in WO2005110485 and U.S. Patent
Publications 20050255079 and 20050255082, all of which are hereby
incorporated by reference.
Biologically Active Agents
[0171] Biologically active agents that can be incorporated into the
graftable pharmaceutically active polymers of the invention include
therapeutic, diagnostic, and prophylactic agents. They can be
naturally occurring compounds, synthetic organic compounds, or
inorganic compounds. Agents that can be incorporated into the
pharmaceutically active polymers of the invention include, but are
not limited to carbohydrates, anti-microbials, antiproliferative
agents, rapamycin macrolides, analgesics, anesthetics,
antiangiogenic agents, vasoactive agents, anticoagulants,
immunomodulators, cytotoxic agents, antiviral agents,
antithrombotic drugs, such as terbrogel and ramatroban, antibodies,
neurotransmitters, psychoactive drugs, oligonucleotides, proteins,
lipids, and combinations thereof. A pharmaceutically active polymer
can also include more than one biologically active agent. For
example, a pharmaceutically active polymer may include two
biologically active agents. The grafting of mixtures and blends of
different pharmaceutically active polymers is also useful in the
articles of the invention.
[0172] In certain embodiments, the biological agent includes two
functional groups selected from hydroxyl, amine, carboxylic acid or
sulfonic acid so that it can be tethered to one or more oligomeric
segments. For example, Ciprofloxacin, which contains a free
secondary amine and carboxyl groups, can be covalently tethered
between two oligomeric segments and incorporated into a polymer
that includes one or more graftable moieties.
[0173] Exemplary therapeutic agents which can be incorporated into
the graftable pharmaceutically active polymers of the invention
include, without limitation, growth hormone, for example human
growth hormone, calcitonin, granulocyte macrophage colony
stimulating factor (GMCSF), ciliary neurotrophic factor, and
parathyroid hormone. Other specific therapeutic agents include
parathyroid hormone-related peptide, somatostatin, testosterone,
progesterone, estradiol, nicotine, fentanyl, norethisterone,
clonidine, scopolomine, salicylate, salmeterol, formeterol,
albeterol, valium, heparin, dermatan, ferrochrome A,
erythropoetins, diethylstilbestrol, lupron, estrogen estradiol,
androgen halotestin, 6-thioguanine, 6-mercaptopurine, zolodex,
taxol, lisinopril/zestril, streptokinase, aminobutylric acid,
hemostatic aminocaproic acid, parlodel, tacrine, potaba, adipex,
memboral, phenobarbital, insulin, gamma globulin, azathioprine,
papein, acetaminophen, ibuprofen, acetylsalicylic acid,
epinephrine, flucloronide, oxycodone percoset, dalgan, phreniline
butabital, procaine, novocain, morphine, oxycodone, aloxiprin,
brofenac, ketoprofen, ketorolac, hemin, vitamin B-12, folic acid,
magnesium salts, vitamine D, vitamin C, vitamin E, vitamin A,
Vitamin U, vitamin L, vitamin K, pantothenic acid,
aminophenylbutyric acid, penicillin, acyclovir, oflaxacin,
amoxicillin, tobramycin, retrovior, epivir, nevirapine, gentamycin,
duracef, ablecet, butoxycaine, benoxinate, tropenzile, diponium
salts, butaverine, apoatropine, feclemine, leiopyrrole,
octamylamine, oxybutynin, albuterol, metaproterenol, beclomethasone
dipropionate, triamcinolone acetamide, budesonide acetonide,
ipratropium bromide, flunisolide, cromolyn sodium, ergotamine
tartrate, and protein or peptide drugs such as TNF antagonists or
interleukin antagonists. For example, the biologically active agent
can be an anti-inflammatory agent, such as an NSAID,
corticosteriod, or COX-2 inhibitor, e.g., rofecoxib, celecoxib,
valdecoxib, or lumiracoxib. The therapeutic agent may also include
antibiotics.
[0174] Exemplary diagnostic agents which can be incorporated into
the graftable pharmaceutically active polymers of the invention
include, without limitation, imaging agents, such as those that are
used in positron emission tomography (PET), computer assisted
tomography (CAT), single photon emission computerized tomography,
X-ray, fluoroscopy, and magnetic resonance imaging (MRI). Suitable
materials for use as contrast agents in MRI include gadolinium
chelates, as well as iron, magnesium, manganese, copper, and
chromium chelates. Examples of materials useful for CAT and X-rays
include iodine based materials.
[0175] Rapamycin Macrolides
[0176] Rapamycin macrolides can be incorporated into the graftable
pharmaceutically active polymers of the invention. Rapamycin
(Sirolimus) is an immunosuppressive lactam macrolide that is
produced by Streptomyces hygroscopicus. See, for example, McAlpine,
J. B., et al., J. Antibiotics 44: 688 (1991); Schreiber, S. L., et
al., J. Am. Chem. Soc. 113: 7433 (1991); and U.S. Pat. No.
3,929,992, incorporated herein by reference. Exemplary rapamycin
macrolides that can be used in the methods and compositions of the
invention include, without limitation, rapamycin, CCI-779,
Everolimus (also known as RAD001), and ABT-578
(40-epi-(N1-tetrazolyl)-rapamycin, see, for example, Pagano T. G.,
Magn. Reson. Chem. 43:174 (2005)). CCI-779 is an ester of rapamycin
(42-ester with 3-hydroxy-2-hydroxymethyl-2-methylpropionic acid),
disclosed in U.S. Pat. No. 5,362,718. Everolimus is an alkylated
rapamycin (40-O-(2-hydroxyethyl)-rapamycin, disclosed in U.S. Pat.
No. 5,665,772.
[0177] Antiproliferative Agents
[0178] Antiproliferative agents can be incorporated into the
graftable pharmaceutically active polymers of the invention.
Exemplary antiproliferative agents which can be used in the methods
and compositions of the invention include, without limitation,
mechlorethamine, cyclophosphamide, iosfamide, melphalan,
chlorambucil, uracil mustard, estramustine, mitomycin C, AZQ,
thiotepa, busulfan, hepsulfam, carmustine, lomustine, semustine,
streptozocin, dacarbazine, cisplatin, carboplatin, procarbazine,
methotrexate, trimetrexate, fluouracil, floxuridine, cytarabine,
fludarabine, capecitabine, azacitidine, thioguanine,
mercaptopurine, allopurine, cladribine, gemcitabine, pentostatin,
vinblastine, vincristine, etoposide, teniposide, topotecan,
irinotecan, camptothecin, 9-aminocamptothecin, paclitaxel,
docetaxel, daunorubicin, doxorubicin, dactinomycin, idarubincin,
plicamycin, mitomycin, amsacrine, bleomycin, aminoglutethimide,
anastrozole, finasteride, ketoconazole, tamoxifen, flutamide,
leuprolide, goserelin, Gleevec.TM. (Novartis), leflunomide
(Pharmacia), SU5416 (Pharmacia), SU6668 (Pharmacia), PTK787
(Novartis), Iressa.TM. (AstraZeneca), Tarceva.TM., (Oncogene
Science), trastuzumab (Genentech), Erbitux.TM. (ImClone), PKI166
(Novartis), GW2016 (GlaxoSmithKline), EKB-509 (Wyeth), EKB-569
(Wyeth), MDX-H2 10 (Medarex),2C4 (Genentech), MDX-447 (Medarex),
ABX-EGF (Abgenix), CI-1033 (Pfizer), Avastin.TM. (Genentech),
IMC-1C11 (ImClone), ZD4190 (AstraZeneca), ZD6474 (AstraZeneca),
CEP-701 (Cephalon), CEP-751 (Cephalon), MLN518 (Millenium), PKC412
(Novartis), 13-cis-retinoic acid, isotretinoin, retinyl palmitate,
4-(hydroxycarbophenyl) retinamide, misonidazole, nitracrine,
mitoxantrone, hydroxyurea, L-asparaginase, interferon alfa,
AP23573, Cerivastatin, Troglitazone, CRx-026DHA-paclitaxel,
Taxoprexin, TPI-287, Sphingosine-based lipids, and mitotane.
[0179] Corticosteroids
[0180] Corticosteroids can be incorporated into the graftable
pharmaceutically active polymers of the invention. Exemplary
corticosteroids which can be used in the methods and compositions
of the invention include, without limitation,
21-acetoxypregnenolone, alclomerasone, algestone, amcinonide,
beclomethasone, betamethasone, betamethasone valerate, budesonide,
chloroprednisone, clobetasol, clobetasol propionate, clobetasone,
clobetasone butyrate, clocortolone, cloprednol, corticosterone,
cortisone, cortivazol, deflazacon, desonide, desoximerasone,
dexamethasone, diflorasone, diflucortolone, difluprednate,
enoxolone, fluazacort, flucloronide, flumethasone, flumethasone
pivalate, flunisolide, flucinolone acetonide, fluocinonide,
fluorocinolone acetonide, fluocortin butyl, fluocortolone,
fluorocortolone hexanoate, diflucortolone valerate,
fluorometholone, fluperolone acetate, fluprednidene acetate,
fluprednisolone, flurandenolide, formocortal, halcinonide,
halometasone, halopredone acetate, hydrocortamate, hydrocortisone,
hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone
phosphate, hydrocortisone 21-sodium succinate, hydrocortisone
tebutate, mazipredone, medrysone, meprednisone, methylprednicolone,
mometasone furoate, paramethasone, prednicarbate, prednisolone,
prednisolone 21-diedryaminoacetate, prednisolone sodium phosphate,
prednisolone sodium succinate, prednisolone sodium
21-m-sulfobenzoate, prednisolone sodium 21-stearoglycolate,
prednisolone tebutate, prednisolone 21-trimethylacetate,
prednisone, prednival, prednylidene, prednylidene
21-diethylaminoacetate, tixocortol, triamcinolone, triamcinolone
acetonide, triamcinolone benetonide and triamcinolone hexacetonide.
Structurally related corticosteroids having similar
anti-inflammatory properties are also intended to be encompassed by
this group.
[0181] NSAIDs
[0182] Non-steroidal anti-inflammatory drugs (NSAIDs) can be
incorporated into the graftable pharmaceutically active polymers of
the invention. Exemplary NSAIDs which can be used in the methods
and compositions of the invention include, without limitation,
naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin,
sulindac, diflunisal, piroxicam, indomethacin, ibuprofen,
nabumetone, choline magnesium trisalicylate, sodium salicylate,
salicylsalicylic acid (salsalate), fenoprofen, flurbiprofen,
ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac,
and tolmetin.
[0183] Analgesics
[0184] Analgesics can be incorporated into the graftable
pharmaceutically active polymers of the invention. Exemplary
analgesics that can be used in the methods and compositions of the
invention include, without limitation, fentanyl, morphine, codeine,
heroin, ethylmorphine, O-carboxymethylmorphine, O-acetylmorphine,
hydrocodone, hydromorphone, oxymorphone, oxycodone, dihydrocodeine,
thebaine, metopon, ethorphine, acetorphine, diprenorphine,
buprenorphine, phenomorphan, levorphanol, ethoheptazine,
ketobemidone, dihydroetorphine and dihydroacetorphine.
[0185] Antimicrobials
[0186] Antimicrobials can be incorporated into the graftable
pharmaceutically active polymers of the invention. Exemplary
antimicrobials which can be used in the methods and compositions of
the invention include, without limitation, penicillin G, penicillin
V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin,
ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin,
piperacillin, azlocillin, temocillin, cepalothin, cephapirin,
cephradine, cephaloridine, cefazolin, cefamandole, cefuroxime,
cephalexin, cefprozil, cefaclor, loracarbef, cefoxitin,
cefmatozole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone,
ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir,
cefpirome, cefepime, chlorhexidine, BAL5788, BAL9141, imipenem,
ertapenem, meropenem, astreonam, clavulanate, sulbactam,
tazobactam, streptomycin, neomycin, kanamycin, paromycin,
gentamicin, tobramycin, amikacin, netilmicin, spectinomycin,
sisomicin, dibekalin, isepamicin, tetracycline, chlortetracycline,
demeclocycline, minocycline, oxytetracycline, methacycline,
doxycycline, erythromycin, azithromycin, clarithromycin,
telithromycin, ABT-773, lincomycin, clindamycin, vancomycin,
oritavancin, dalbavancin, teicoplanin, quinupristin and
dalfopristin, sulphanilamide, para-aminobenzoic acid, sulfadiazine,
sulfisoxazole, sulfamethoxazole, sulfathalidine, linezolid,
nalidixic acid, oxolinic acid, norfloxacin, perfloxacin, enoxacin,
ofloxacin, ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin,
grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin,
gatifloxacin, moxifloxacin, gemifloxacin, sitafloxacin,
metronidazole, daptomycin, garenoxacin, ramoplanin, faropenem,
polymyxin, tigecycline, AZD2563, and trimethoprim.
[0187] Membrane Active Biocides
[0188] One exemplary, non-limiting class of anti-microbials useful
in the polymers and articles of the invention are membrane active
biocides. Membrane active biocides which can be used in the
polymers and articles of the invention include, without limitation,
chlorhexidine, polymyxin B-nonapeptide, bacitracin, monobactams
(e.g., aztreonam, carumonam, or tigemonan), benzalkonium salts, and
metal chelators, such as ethylenediaminetetraacetate (EDTA).
[0189] Fluoroquinolones
[0190] A second exemplary, non-limiting class of anti-microbials
are fluoroquinolones. Examples of fluoroquinolones useful in the
polymers and articles of the invention include, but are not limited
to, those described in patent publications BE870576; DE3142854;
EP047005; EP206283; BE887574; EP221463; EP140116; EP131839;
EP154780; EP078362; EP310849; EP520240; and U.S. Pat. Nos.
4,448,962; 4,499,091; 4,704,459; 4,795,751; 4,668,784; and
5,532,239, each of which is incorporated herein by reference.
[0191] Additional exemplary fluoroquinolones which can be used in
the polymers and articles of the invention include, without
limitation, ciprofloxacin (commercially available as Cipro.RTM.),
enrofloxacin (commercially available as Baytril.RTM.), enoxacin
(commercially available as Penetrex.RTM.), gatifloxacin
(commercially available as Tequin.RTM.), gemifloxacin (commercially
available as Factive.RTM.), levofloxacin (commercially available as
Levaquin.RTM.), lomefloxacin (commercially available as
Maxaquin.RTM.), moxifloxacin (commercially available as
Avelox.RTM.), norfloxacin (commercially available as Noroxin.RTM.),
ofloxacin (commercially available as Floxin.RTM.), sparfloxacin
(commercially available as Zagam.RTM.), trovafloxacin (commercially
available as Trovan.RTM.), difloxacin, cinofloxacin, pefloxacin,
tosufloxacin, temafloxacin, fleroxacin, amifloxacin, binfloxacin,
danofloxacin, marbofloxacin, ruflocaxin, and sarafloxacin.
[0192] Local Anesthetics
[0193] Local anesthetics can be incorporated into the graftable
pharmaceutically active polymers of the invention. Exemplary local
anesthetics that can be used in the methods and compositions of the
invention include, without limitation, cocaine, procaine,
lidocaine, prilocalne, mepivicaine, bupivicaine, articaine,
tetracaine, chloroprocaine, etidocaine, and ropavacaine.
[0194] Antispasmodics
[0195] Antispasmodics can be incorporated into the graftable
pharmaceutically active polymers of the invention. Exemplary
antispasmodics that can be used in the methods and compositions of
the invention include, without limitation, anticholinergics and
other therapeutics including: atropine, belladonna, Bentyl.RTM.
(dicyclomine), Cystospaz.RTM. (hyoscyamine), darifenacin,
Detrol.RTM. (tolterodine), Ditropan.RTM. (oxybutynin),
Donnatal.RTM., Donnazyme.RTM., fasudil, Flexeril.RTM.
(clobenzaprine), glycopyrrolate, Levsin.RTM., Levsinex.RTM.,
Librax.RTM., Malcotran.RTM. or Novatrine.RTM. (homatropine
methylbromide), Novartin.RTM. (hydergine), oxyphencyclimine,
Pamine.RTM.) (methscopolamine), prozapine, pinaverium, solifenacin
succinate, tiquizium, and trospium.
Coated Articles
[0196] A wide variety of articles can be coated with the graftable
pharmaceutically active polymers of the invention. For example,
articles which contact bodily fluids, such as medical devices can
be coated to improve their biocompatibility. The medical devices
include, without limitation, catheters, guide wires, vascular
stents, micro-particles, electronic leads, probes, sensors, drug
depots, transdermal patches, vascular patches, blood bags, and
tubing. The medical device can be an implanted device, percutaneous
device, or cutaneous device. Implanted devices include articles
that are fully implanted in a patient, i.e., are completely
internal. Percutaneous devices include items that penetrate the
skin, thereby extending from outside the body into the body.
Cutaneous devices are used superficially. Implanted devices
include, without limitation, prostheses such as pacemakers,
electrical leads such as pacing leads, defibrillarors, artificial
hearts, ventricular assist devices, anatomical reconstruction
prostheses such as breast implants, artificial heart valves, heart
valve stents, pericardial patches, surgical patches, coronary
stents, vascular grafts, vascular and structural stents, vascular
or cardiovascular shunts, biological conduits, pledges, sutures,
annuloplasty rings, stents, staples, valved grafts, dermal grafts
for wound healing, orthopedic spinal implants, orthopedic pins,
intrauterine devices, urinary stents, maxial facial reconstruction
plating, dental implants, intraocular lenses, clips, sternal wires,
bone, skin, ligaments, tendons, and combination thereof.
Percutaneous devices include, without limitation, catheters or
various types, cannulas, drainage tubes such as chest tubes,
surgical instruments such as forceps, retractors, needles, and
gloves, and catheter cuffs. Cutaneous devices include, without
limitation, burn dressings, wound dressings and dental hardware,
such as bridge supports and bracing components.
Combination Therapies
[0197] Any of the polymers and articles of the invention may
include two or more biologically active agents. For example, a
graftable, pharmaceutically active polymer of the invention may
include two or more biologically active agents. In another example,
two or more pharmaceutically active polymers that each include a
different biologically active agent can be used in the grafted
articles of the invention.
[0198] In a non-limiting example, the polymers and articles of the
invention can include two or more anti-microbials. The grafted
articles of the invention can also include two different
pharmaceutically active polymers that each include a different
anti-microbial. One exemplary, non-limiting combination useful in
the polymers and articles of the invention is that of a membrane
active biocide and a fluoroquinolone. For example, the polymers and
articles of the invention can include both a membrane active
biocide and a fluoroquinolone. In some embodiments, an article of
the invention may have grafted to its surface pharmaceutically
active polymers that include a membrane active biocide and other
pharmaceutically active polymers that include a fluoroquinolone. In
certain embodiments, the two or more pharmaceutically active
polymers may be blended or combined. The mixture or combination of
graftable polymers can be grafted to the surface of an article. In
yet another embodiment of the invention, the graftable
pharmaceutically active polymers that include different
biologically active agents are grafted separately onto the surface.
In certain polymers and articles of the invention, the membrane
active biocide is chlorhexidine and the fluoroquinolone is
ciprofloxacin.
[0199] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how the methods and compounds claimed herein are
performed, made, and evaluated, and are intended to be purely
exemplary of the invention and are not intended to limit the scope
of what the inventors regard as their invention.
Example 1
Synthesis of Polysilicones Including an Activated Silicon Grafting
Moiety with Amine End Groups
[0200] Polysilicones including activated silicon centers and amine
end groups were used in the synthesis of graftable,
pharmaceutically active polymers. A polysilicone including an
activated silicon center as a grafting moiety was prepared
according to Scheme 2. A polysilicone (Compound (8)) was treated
with an amine-containing silicon reagent such as compound (9) to
yield a polysilicone that has amine end groups (compound (2)). In
this procedure, compound (8) was stripped of water by heating to
100.degree. C. under vacuum (2-5 mm Hg) for 1 hour. The temperature
was then reduced to 75.degree. C. and aminopropyltrialkoxysilane
(compound 9) was then added. The system remained under vacuum for 4
hours to remove the ethanol formed from the condensation process. A
clear colorless fluid was then obtained. .sup.1H NMR (400 MHz,
CDCl.sub.3). .delta.: 3.75 (q, OCH.sub.2CH.sub.3), 2.64 (t,
CH.sub.2CH.sub.2CH.sub.2), 1.19 (t, OCH.sub.2CH.sub.3, 0.00 (s,
Si(CH.sub.3).
##STR00018##
Example 2
Synthesis of Polysilicones Including an Activated Silicon Grafting
Moiety with Hydroxy End Groups
[0201] Polysilicones including activated silicon centers and
hydroxy end groups may be used in the synthesis of graftable,
pharmaceutically active polymers. A polysilicone including an
activated silicon center as a grafting moiety may be prepared
according to Scheme 3. A polysilicone (Compound (8)) may be treated
with a hydroxy-containing silicon reagent such as compound (10) to
yield an activated polysilicone that has hydroxy end groups
(compound (4)).
##STR00019##
Example 3
Synthesis of Polysilicones Including a Hydridosilane Grafting
Moiety with Amine End Groups
[0202] Monomers including hydridosilanes are suitable for the
synthesis of graftable, pharmaceutically active polymers and can be
prepared according to Scheme 4. A silane reagent such as compound
(11) can be used in a Pt-catalyzed hydrosilylation of an olefinic
substrate such as an N-protected allylamine (compound (12)). The
resulting product (compound (13)) may then be treated with a
reducing agent such as LiAlH.sub.4 followed by N-deprotection to
afford the desired hydridosilane product (compound (5)).
##STR00020##
Example 4
Synthesis of a Diamine or a Diol Including an Azide Grafting
Moiety
[0203] Diamines and diols including a grafting moiety including an
azide were prepared according to Scheme 5. A precursor including an
activated carboxylic acid group (compound (14)) was treated with
reagents such as compounds (15) and (16). These latter reagents
employed suitable protecting groups (PG) when required on the
terminal amine and hydroxyl functional groups, respectively.
Deprotection subsequently afforded the corresponding monomers (6)
and (7). Monomer (6) is also referred to as "Reagent A" or "SANPAH"
and is commercially available from Thermo Scientific.
##STR00021##
[0204] For example, diethanolamine (compound (16)) was added
dropwise to a cooled (0.degree. C.) solution of compound (14) in
DMF. The orange solution was stirred overnight with warming. The
solvent was removed under reduced pressure. The resulting solid
residue was dissolved in ethyl acetate and transferred to a
separatory funnel where the organic layer was washed with brine.
The combined aqueous layers were back extracted with ethyl acetate.
The organic layers were combined, dried with sodium sulfate and the
solvent was removed under reduced pressure to yield compound (7)
which was used without further purification. .sup.1H NMR (400 MHz,
CDCl.sub.3). 6: 7.78 (s, 1H, Ph-H), 7.06 (dd, J=2.76 Hz, J=8.1 Hz,
1H, Ph-H), 6.8 (d, J=8.1 Hz, 1H, Ph-H), 3.76 (dt, J=5.0 Hz, J=30.8
Hz, 4H, NCH.sub.2CH.sub.2OH), 3.47 (dt, J=5.0 Hz, J=30.8 Hz, 4H,
NCH.sub.2CH.sub.2OH), 3.25 (t, J=7.0 Hz, 2H,
Ph-NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO), 2.38 (t, J=7.32
Hz, 2H, Ph-NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO), 1.67 (m,
4H, Ph-NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO), 1.42 (m, 2H,
Ph-NHCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CO), 1.18 (bs, 2H,
OH); .sup.13C NMR (400 MHz, CDCl.sub.3) .delta.: 175.3, 143.6,
128.5, 128.0, 116.2, 115.8, 62.0, 61.0, 52.2, 50.6, 43.2, 29.0,
26.9, 24.9.
Example 5
Synthesis of Graftable, Pharmaceutically Active Polymers Including
Activated Silicon Grafting Moieties
##STR00022## ##STR00023##
[0206] Graftable pharmaceutically active polymers including
activated silicon grafting moieties are synthesized by
prepolymerizing a mixture of the selected polysilicone (e.g.
compounds (2) or (4)) in polycaprolactone diol (PCL) with a
diisocyanate in the presence of a catalyst. In the second stage of
polymerization, the pharmaceutically-active component and any
additional catalyst are added to afford the desired graftable,
pharmaceutically active polymers.
[0207] The synthesis of a polymer from reagents that include
compound (2), PCL, and 2,2,4-trimethylhexamethylene diisocyanate
(THDI) was accomplished according to the following procedure:
[0208] A mixture of 10% (w/w) compound (2) in PCL (2.0 equivalents
relative to CP), THDI (3.1 equivalents), and dibutyltin dilaurate
(DBTL; 0.2 equivalents) was heated in dimethylsulfoxide (DMSO) at
65.degree. C. for 1.5 hours. At that time, a DMSO solution of
ciprofloxacin (CP), or a derivative thereof, and an additional 0.12
equivalents of DBTL was added. The reaction continued to stir at
65.degree. C. for four hours and then stirred at ambient
temperature (20-25.degree. C.) for 17 hours. Methanol was then
added to the reaction and the addition of solvents allows the
precipitation of the pharmaceutically-active polymer from the
reaction mixture. The polymer was redissolved in solvent and again
precipitated using solvents. The dissolution/precipitation cycle
was repeated two additional times to afford the desired polymer.
Variation of each reagent affords the different graftable polymers
of the invention.
[0209] Polymers (17), (18), (19), and (20), which include
ciprofloxacin as the biologically active agent, are depicted in
Scheme 6 and were prepared according to this procedure. Tables 2
and 3 show additional examples of pharmaceutically active polymers
including activated silicon grafting moieties that are prepared
according to this procedure and by varying reagent amounts as
listed in the table.
[0210] The drug-releasing properties of these polymers may be
measured using the Minimum Inhibitory Concentration (MIC) assay or
by using HPLC. FIG. 1 shows that polymers (17), which include from
5-50 w/w % activated silicon grafting moieties, are effective
against E. coli over a twelve week period. FIG. 2 shows that these
same polymers effectively release ciprofloxacin over a twelve week
time frame. FIGS. 3 and 4 show MIC and HPLC data, respectively, for
polymers (19). The data demonstrate that these polymers also
effectively release ciprofloxacin, as measured over 12 weeks.
TABLE-US-00002 TABLE 2 (2) ##STR00024## Polymerization % w/w
Pre-polymerization (4 h at 65.degree. C.; Polymer polysilicone/PCL
(1.5 h at 65.degree. C.) 17 h at 23.degree. C.) Mol. Wt./T.sub.m
18a 2 Siloxane/PCL = 2.0 eq. CP = 1.0 eq. M.W. = 29.3 kg/mol THDI =
3.1 eq. DBTL = 0.12 eq. Melt Temp. = 50.56.degree. C. DBTL = 0.2
eq. 18b 5 Siloxane/PCL = 2.0 eq. CP = 1.0 eq. M.W. = 26.9 kg/mol
THDI = 3.1 eq. DBTL = 0.12 eq. Melt Temp. = 50.46.degree. C. DBTL =
0.2 eq. 18c 20 Siloxane/PCL = 2.0 eq. CP = 1.0 eq. M.W. = 27.1
kg/mol THDI = 3.1 eq. DBTL = 0.12 eq. Melt Temp. = 50.06.degree. C.
DBTL = 0.2 eq. 18d 30 Siloxane/PCL = 2.0 eq. CP = 1.0 eq. M.W. =
19.9 kg/mol THDI = 3.1 eq. DBTL = 0.12 eq. Melt Temp. =
55.21.degree. C. DBTL = 0.2 eq. 18e 50 Siloxane/PCL = 2.0 eq. CP =
1.0 eq. M.W. = 14.7 kg/mol THDI = 3.1 eq. DBTL = 0.12 eq. Melt
Temp. = 55.23.degree. C. DBTL = 0.2 eq.
TABLE-US-00003 TABLE 3 (4) ##STR00025## Polymerization % w/w
Pre-polymerization (4 h at 65.degree. C.; Polymer polysilicone/PCL
(1.5 h at 65.degree. C.) 17 h at 23.degree. C.) Mol. Wt./T.sub.m
20a 2 Siloxane/PCL = 2.0 eq. CP = 1.0 eq. M.W. = 33.22 kg/mol THDI
= 3.1 eq. DBTL = 0.12 eq. Melt Temp. = 46.65.degree. C. DBTL = 0.2
eq. 20b 5 Siloxane/PCL = 2.0 eq. CP = 1.0 eq. M.W. = 28.23 kg/mol
THDI = 3.1 eq. DBTL = 0.12 eq. Melt Temp. = 49.59.degree. C. DBTL =
0.2 eq. 20c 10 Siloxane/PCL = 2.0 eq. CP = 1.0 eq. M.W. = 27.22
kg/mol THDI = 3.1 eq. DBTL = 0.12 eq. Melt Temp. = 46.40.degree. C.
DBTL = 0.2 eq. 20d 20 Siloxane/PCL = 2.0 eq. CP = 1.0 eq. M.W. =
31.83 kg/mol THDI = 3.1 eq. DBTL = 0.12 eq. Melt Temp. =
44.06.degree. C. DBTL = 0.2 eq. 20e 30 Siloxane/PCL = 2.0 eq. CP =
1.0 eq. M.W. = 24.78 kg/mol THDI = 3.1 eq. DBTL = 0.12 eq. Melt
Temp. = 45.05.degree. C. DBTL = 0.2 eq. 20f 50 Siloxane/PCL = 2.0
eq. CP = 1.0 eq. M.W. = 20.22 kg/mol THDI = 3.1 eq. DBTL = 0.12 eq.
Melt Temp. = 45.40.degree. C. DBTL = 0.2 eq.
Example 6
Synthesis of Graftable, Pharmaceutically Active Polymers Including
Hydridosilane Grafting Moieties
[0211] Pharmaceutically active polymers including polyurethane
segments and hydridosilane grafting moieties are prepared by
prepolymerizing a mixture of the selected hydridosilane monomer
(e.g. compound (5)) with a diisocyanate in the presence of a
catalyst. Other compounds such as PCL can be included in the
prepolymerization. In the second stage of polymerization, the
pharmaceutically-active component and any additional catalyst are
added to afford the desired pharmaceutically active polymers.
Example 7
Synthesis of Graftable, Pharmaceutically Active Polymers Including
UV-Labile Grafting Moieties
##STR00026## ##STR00027##
[0213] Pharmaceutically active polymers including polyurethane
segments and UV-labile grafting moieties were prepared by
prepolymerizing a mixture of the selected UV-labile monomer (e.g.
compound (6) or compound (7)) with a diisocyanate in the presence
of a catalyst. Reagent A (also referred to as "SANPAH") is another
UV-labile monomer that is useful in the polymers and articles of
the invention. Other compounds such as PCL may be optionally
included in the prepolymerization. In the second stage of
polymerization, the pharmaceutically-active component and any
additional catalyst were added to afford the desired
pharmaceutically active polymers.
[0214] Scheme 7 shows Polymer (21) which includes ciprofloxacin as
the biologically active agent and is prepared according to this
procedure. Table 4 shows additional examples of pharmaceutically
active polymers including UV-labile grafting moieties that are
prepared according to this procedure.
TABLE-US-00004 TABLE 4 Polymer Prepolymerization Polymerization
Stage Molecular Weight Melt Temp. 21a PCL = 2.0 equiv. CP.sub.2TEG
= 1.0 equiv. 33.21 kg/mol 44.12.degree. C. THDI = 3.2 equiv. DBTL =
0.12 equiv. DBTL = 0.2 equiv. 4 hrs 65.degree. C., 17 hrs R.T.
Reagent A = 0.02 equiv. 1.5 hours 65.degree. C. 21b PCL = 2.0
equiv. CP.sub.2TEG = 1.0 equiv. 37.49 kg/mol 34.86.degree. C. THDI
= 3.2 equiv. DBTL = 0.12 equiv. DBTL = 0.2 equiv. 4 hrs 65.degree.
C., 17 hrs R.T. Reagent A = 0.05 equiv. 1.5 hours 65.degree. C. 21c
PCL = 2.0 equiv. CP.sub.2TEG = 1.0 equiv. 38.04 kg/mol
44.48.degree. C. THDI = 3.2 equiv. DBTL = 0.12 equiv. DBTL = 0.2
equiv. 4 hrs 65.degree. C., 17 hrs R.T. Reagent A = 0.1 equiv. 1.5
hours 65.degree. C. 21d PCL = 2.0 equiv. CP.sub.2TEG = 1.0 equiv.
33.59 kg/mol 36.25.degree. C. THDI = 3.2 equiv. DBTL = 0.12 equiv.
DBTL = 0.2 equiv. 4 hrs 65.degree. C., 17 hrs R.T. Reagent A = 0.2
equiv. 1.5 hours 65.degree. C. ##STR00028##
Example 8
Synthesis of Graftable, Pharmaceutically Active Polymers Including
Chlorhexidine and Activated Silicon Grafting Moieties
##STR00029##
[0216] Graftable pharmaceutically active polymers that include
chlorhexidine as the biologically active agent are prepared in a
manner analogous to the ciprofloxacin-containing polymers of
Example 5. The synthesis of chlorhexidine-containing polymers is
described below. Scheme 8 depicts graftable polymers 22 and 23,
each of which includes chlorhexidine.
[0217] A mixture of 10% (w/w) compound (2) in PCL (2.0 equivalents
relative to CH), THDI (3.1 equivalents), and dibutyltin dilaurate
(DBTL; 0.2 equivalents) was heated in dimethylsulfoxide (DMSO) at
65.degree. C. for 1.5 hours. At that time, a DMSO solution of
chlorhexidine (CH), or derivatives thereof, and an additional 0.12
equivalents of DBTL was added. The reaction continued to stir at
65.degree. C. for four hours and then stirred at ambient
temperature (20-25.degree. C.) for 17 hours. Methanol was then
added to the reaction and the addition of solvents allows the
precipitation of the pharmaceutically-active polymer from the
reaction mixture. The polymer was redissolved in solvent and again
precipitated using solvents. The dissolution/precipitation cycle
was repeated two additional times to afford the desired polymer.
Variation of each reagent affords the different graftable polymers
of the invention. Table 5 shows additional data for polymers 22 and
23.
[0218] The drug-releasing properties of these polymers may be
measured using the Minimum Inhibitory Concentration (MIC) assay or
by using HPLC.
TABLE-US-00005 TABLE 5 Polymer Prepolymerization Polymerization
Stage Molecular Weight Melt Temp. 22 PCL = 2.0 THDI = 3.1;
Chlorhexidine = 1.0 22.86 kg/mol 49.27.degree. C. DBTL = 0.2 DBTL =
0.12 1.5 hours 65.degree. C. 4 hrs 65.degree. C., 17 hrs R.T. 23
PCL = 2.0 equiv. Chlorhexidine = 1.0 24.21 kg/mol 50.35.degree. C.
THDI = 3.1 equiv. DBTL = 0.12 DBTL = 0.2 equiv. 4 hrs 65.degree.
C., Reagent A = 0.02 equiv. 17 hrs R.T. 1.5 hours 65.degree. C.
##STR00030##
Example 9
Synthesis of Graftable, Pharmaceutically Active Polymers Including
Chlorhexidine and UV-Labile Grafting Moieties
##STR00031##
[0220] Pharmaceutically active polymers including chlorhexidine,
polyurethane segments and UV-labile grafting moieties can be
prepared in a manner analogous to Example 7. Scheme 9 depicts a
chlorhexidine-containing graftable polymer (24) and the synthesis
of this polymer is further described below. Table 6 provides
additional data for Polymer 24(a)
[0221] A mixture of 2% (w/w) Reagent A in PCL (2.0 equivalents
relative to CH), THDI (3.1 equivalents), and dibutyltin dilaurate
(DBTL; 0.2 equivalents) was heated in dimethylsulfoxide (DMSO) at
65.degree. C. for 1.5 hours. At that time, a DMSO solution of
chlorhexidine (CH) and an additional 0.12 equivalents of DBTL was
added. The reaction continued to stir at 65.degree. C. for four
hours and then stirred at ambient temperature (20-25.degree. C.)
for 17 hours. Methanol was then added to the reaction and the
addition of solvents allows the precipitation of the
pharmaceutically-active polymer from the reaction mixture. The
polymer was redissolved in solvent and again precipitated using
solvents. The dissolution/precipitation cycle was repeated two
additional times to afford the desired polymer. Variation of each
reagent affords the different graftable polymers of the
invention.
TABLE-US-00006 TABLE 6 Polymer Prepolymerization Polymerization
Stage Molecular Weight Melt Temp. 24a PCL = 2.0 THDI = 3.1;
Chlorhexidine = 1.0 22.86 kg/mol 49.27.degree. C. DBTL = 0.2 DBTL =
0.12 1.5 hours 65.degree. C. 4 hrs 65.degree. C., 17 hrs R.T.
##STR00032##
Example 10
Procedure for Grafting a Graftable, Pharmaceutically Active Polymer
Including Activated Polysiloxane Grafting Moieties to a
Polysilicone Polymer
[0222] A graftable polymer including an activated silicon grafting
moiety, such as polymers (17)-(20) and other polymers prepared
according to Example 5, was grafted to the surface of base polymer
such as polysilicone according to the following procedure. A
polysilicone surface was treated with 10M aqueous NaOH for 2 hours
at ambient temperature. The silicone surface was then washed twice
with deionized water (e.g. water obtained after purification
through a Millipore system, here after referred to as Milli-Q
water) and then dried in an oven at 120.degree. C. for two hours. A
solution of the graftable polymer in THF was prepared and dipping
of the polysilicone surface into this solution allowed for coating
of the surface. This procedure was repeated in order to achieve the
desired coating thickness. Once the desired coating thickness was
achieved, the grafted polymer was allowed to cure for a minimum of
16 hours at ambient temperature and under conditions of 10-50%
relative humidity.
[0223] FIG. 5 shows drug release by polymer (18), containing 20%
w/w activated silicone grafting moieties, grafted to silicone
tubing. The data show that the grafted polymer is effective at
releasing drugs as measured over a twelve week period.
Example 11
Procedure for Grafting a Graftable, Pharmaceutically Active Polymer
Including Activated Polysiloxane Grafting Moieties to a
Polysilicone Polymer Using Acetoxysilane Additives
[0224] A graftable polymer including an activated silicon grafting
moiety, such as polymers (17)-(20) and other polymers prepared
according to Example 5, was grafted to the surface of base polymer
such as polysilicone according to the following procedure and
incorporates the use of acetoxysilane additives. A polysilicone
surface was treated with 10M aqueous NaOH for 2 hours at ambient
temperature. The silicone surface was then washed twice with
deionized water (e.g. water obtained after purification through a
Millipore system, hereafter referred to as Milli-Q water) and then
dried in an oven at 120.degree. C. for two hours. A solution of
graftable polymer is THF was prepared as described in Example 8. A
second solution of the graftable polymer and acetoxysilane
additives in THF was also prepared by combining 70 g of
methyltriacetoxysilane, 70 g of ethyltriacetoxysilane, 5 g of the
graftable polymer, and 1 g of acetic acid in 100 mL THF. Other
mixtures and ratios of alkoxy- or acetoxysilane reagents may be
used.
[0225] The first solution was then mixed with the second solution
in a 10:1 (v/v) ratio to yield a mixed solution. The polysilicone
surface was then dipped into this mixed solution and the resulting
coated polysilicone surface was dried under ambient conditions.
This procedure was repeated multiple times in order to achieve the
desired coating thickness. Once the desired coating thickness was
achieved, the grafted polymer was allowed to cure for a minimum of
16 hours at ambient temperature and under conditions of 10-50%
relative humidity.
[0226] FIG. 6 shows MIC data for polymer (18) grafted to silicone
tubing using triacetoxymethylsilane. These grafted polymers remain
effective against E. coli as measured over a thirteen week
period.
Example 12
Procedure for Grafting a Pharmaceutically Active Polymer Including
Hydridosilane Grafting Moieties to a Latex Polymer
[0227] A graftable polymer including a hydridosilane grafting
moiety, such as those prepared in Example 6, was grafted to the
surface of a base polymer, such as latex, according to the
following procedure. A solution of the graftable polymer and a
Pt-containing catalyst (e.g. chloroplatinic acid or Karstedt's
catalyst) in THF was prepared. A latex surface was then dipped into
the solution to coat the surface and then dried completely under
ambient conditions.
Example 13
Procedure for Grafting a Pharmaceutically Active Polymer Including
UV Labile Grafting Moieties to a Base Polymer
[0228] A graftable polymer that includes a UV labile grafting
moiety, such as polymer (21) and other polymers prepared according
to Example 7, was grafted to the surface of a base polymer such as
silicone, polyethylene, polyvinylchloride, or polyurethane
according to the following procedure. A solution of the graftable
polymer in THF was prepared. A base polymer surface was then dipped
into the solution to coat the surface and dried completely under
ambient conditions. The coated polymer was then irradiated under
inert atmosphere (e.g. Ar or N.sub.2 atmosphere) using a light
source that provides wavelengths between 300-460 nm. The grafted
polymer was cured for 16 hours under ambient conditions.
[0229] FIG. 7 shows MIC data for polymers (21) grafted to a
polyurethane surface. The polymer can contain from 2%-20% (w/w) of
the UV labile grafting moiety. The graph shows that the grafted
polymers are effective against E. Coli over a thirteen week period
and that polymers that include a higher percentage of grafting
moieties have lower MIC values.
[0230] FIG. 8 shows MIC data for polymers (21) grafted to
polyvinylchloride (PVC). These grafted polymers remain active
against E. coli as measured over a time period that exceeds 90
days.
[0231] FIG. 9 shows that polymers (21) grafted to polyurethanes or
to silicone can continue to release ciprofloxacin over a twelve
week period.
Example 14
Preparation of Grafted Articles Useful in Combination
Therapies-Grafting to Silicone Surfaces
[0232] A mixture of a graftable polymer that includes an activated
silicon grafting moiety and ciprofloxacin as the biologically
active agent (e.g., a polymer prepared according to Example 5) and
a second graftable polymer that includes an activated silicon
grafting moiety and chlorhexidine as the biologically active agent
(e.g., a polymer prepared according to Example 8) can be grafted to
the surface of base polymer such as polysilicone according to the
following procedure. A polysilicone surface can be treated with 10M
aqueous NaOH for 2 hours at ambient temperature. The silicone
surface can then be washed twice with Milli-Q water and dry in an
oven at 120.degree. C. for two hours. A solution of the two
different graftable polymers in THF can then be prepared. Dipping
of the polysilicone surface into this solution can allow for
coating of the surface. This procedure can be repeated in order to
achieve the desired coating thickness. Once the desired coating
thickness is achieved, the grafted polymer can then cure for a
minimum of 16 hours at ambient temperature and under conditions of
10-50% relative humidity. This procedure can afford the desired
grafted article.
Example 15
Procedure for Grafting a Pharmaceutically Active Polymer Including
UV Labile Grafting Moieties to a Base Polymer
[0233] A mixture of a graftable polymer that includes a UV labile
grafting moiety and ciprofloxacin as the biologically active agent
(e.g., a polymer prepared according to Example 7) and a second
graftable polymer that includes a UV labile grafting moiety and
chlorhexidine as the biologically active agent (e.g., a polymer
prepared according to Example 9) can be grafted to the surface of a
base polymer such as silicone, polyethylene, polyvinylchloride, or
polyurethane according to the following procedure. A solution of
the two different graftable polymers in THF can then be prepared. A
base polymer surface can then be dipped into the solution to coat
the surface and can then be dried completely under ambient
conditions. The coated polymer can then be irradiated under inert
atmosphere (e.g. Ar or N.sub.2 atmosphere) using a light source
that provides wavelengths between 300-460 nm. The grafted polymer
can then cure for 16 hours under ambient conditions. This procedure
can then afford the grafted article.
Example 16
Grafting of a Pharmaceutically Active Polymer Including an
Activated Polysiloxane Moiety to a Ceramic Surface
[0234] A graftable polymer including an activated polysiloxane
grafting moiety, such as those prepared in Example 5, may be
grafted to the surface of a ceramic base such as TiO.sub.2 using a
procedure such as that described in U.S. Pat. No. 6,033,781. A
solution including the graftable polymer in an organic solvent such
as THF or ethanol may be added to a solution of the TiO.sub.2 and
alkoxide base. The reaction may be allowed to stir for 2-16 hours
and the coated TiO.sub.2 may then be dried under inert atmosphere
conditions. The process may be repeated until the desired coating
thickness is achieved.
Example 17
Grafting of a Pharmaceutically Active Polymer Including UV-Labile
Grafting Moieties to a Metal Surface
[0235] A graftable polymer including a UV labile grafting moiety,
such as those prepared in Example 7, can be grafted to a metal
surface, such as stainless steel, using photolytic activation. A
solution of the graftable polymer in THF can be prepared. A metal
surface can then be dipped into the solution to coat the surface
and then dried completely under ambient conditions. The coated
polymer can then be irradiated under inert atmosphere (e.g. Ar or
N.sub.2 atmosphere) using a light source that provides wavelengths
between 300-460 nm. The grafted polymer can then be cured for 16
hours under ambient conditions.
Example 18
Grafting of a Pharmaceutically Active Polymer Including UV-Labile
Grafting Moieties to a Metal Surface Using Thermolytic
Activation
[0236] The polymers prepared in Example 7 include azide-containing
grafting moieties that may also be grafted to a surface under
thermolytic activation. These polymers can be grafted to a metal
surface, such as stainless steel, according to procedures such as
that described in U.S. Pat. No. 3,666,536, herein incorporated by
reference. A solution of the graftable polymer in THF can be
prepared. A metal surface can then be dipped into the solution to
coat the surface and can then be dried completely under ambient
conditions. The coated polymer can then be heated under inert
atmosphere (e.g. Ar or N.sub.2 atmosphere) at temperatures that
range between 300-500.degree. C. The grafted polymer can then be
cured for 16 hours under ambient conditions.
Example 19
Grafting of Pharmaceutically Active Polymers Including UV-Labile
Grafting Moieties to Base Polymers Using Tie Coats
[0237] A graftable polymer, such as those prepared in Example 7,
was grafted to the surface of a base polymer, such as silicone,
according to the following procedure. A 1:2 (Solution A) and 1:2
(Solution B) weight percent solution of the graftable polymer and
tie coat in THF was prepared. The polysilicone surface was then
dipped into Solution A first, and the resulting coated polysilicone
surface was then dried under ambient conditions. The resulting
treated surface was then dipped into the second Solution B and
dried under ambient conditions. The second dipping procedure using
Solution B can be repeated multiple times in order to achieve the
desired coating thickness. Once the desired coating thickness was
achieved, the grafted polymer was allowed to cure for a minimum of
16 hours at ambient temperature and under conditions of 10-50%
relative humidity.
[0238] In this procedure, the graftable polymer:tie coat ratios
were varied. For example, a 1:2 and 1:1 weight percent solution of
the graftable polymer and tie coat in THF were used, respectively
for Solutions A and B. Alternatively, a single weight percent
solution (e.g., 1:1) was used for each dipping procedure. The
effect of varying the polymer:tie coat ratio can be seen in FIG.
10. In this figure, "Epidel 1" refers to silicone tubing coated
with a 2:1 w/w formulation of polymer:tie coat and "Epidel 2"
refers to silicone tubing coated with a 1:2 w/w formulation of
polymer:tie coat. These coated articles are challenged with
Staphylococcus aureus, and the results thus obtained are compared
to results using uncoated silicone tubing and silver coated tubing.
Both Epidels 1 and 2 are more effective against S. aureus than
uncoated or silver coated tubing, and it can be seen that the
decrease in S. aureus counts occurs more rapidly using Epidel 1
compared to Epidel 2. Without being bound by theory, it is thought
that increasing the amount of tie-coat used leads to decreased
amounts of pharmaceutically active polymer on the surface, thereby
affecting rates of hydrolysis and relase of the pharmaceutically
active agent (in this case, ciprofloxacin). The application of a
tie-coat layer separately from a graftable polymer layer versus the
coating of an article with an admixture of tie-coat and polymer can
similarly affect the amount of pharmaceutically active polymer
present on the surface of a coated article, with a greater amount
of pharmaceutically active polymer present using the former
approach.
Other Embodiments
[0239] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each independent publication or patent
application was specifically and individually indicated to be
incorporated by reference.
[0240] While the invention has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications and this application is intended
to cover any variations, uses, or adaptations of the invention
following, in general, the principles of the invention and
including such departures from the present disclosure that come
within known or customary practice within the art to which the
invention pertains and may be applied to the essential features
hereinbefore set forth, and follows in the scope of the claims.
[0241] Other embodiments are within the claims.
* * * * *